Affinity modulation of platelet integrin alphaIIbbeta3 by beta3-endonexin, a selective binding partner of the beta3 integrin cytoplasmic tail.

Platelet agonists increase the affinity state of integrin alphaIIbbeta3, a prerequisite for fibrinogen binding and platelet aggregation. This process may be triggered by a regulatory molecule(s) that binds to the integrin cytoplasmic tails, causing a structural change in the receptor. beta3-Endonexin is a novel 111-amino acid protein that binds selectively to the beta3 tail. Since beta3-endonexin is present in platelets, we asked whether it can affect alphaIIbbeta3 function. When beta3-endonexin was fused to green fluorescent protein (GFP) and transfected into CHO cells, it was found in both the cytoplasm and the nucleus and could be detected on Western blots of cell lysates. PAC1, a fibrinogen-mimetic mAb, was used to monitor alphaIIbbeta3 affinity state in transfected cells by flow cytometry. Cells transfected with GFP and alphaIIbbeta3 bound little or no PAC1. However, those transfected with GFP/beta3-endonexin and alphaIIbbeta3 bound PAC1 specifically in an energy-dependent fashion, and they underwent fibrinogen-dependent aggregation. GFP/beta3-endonexin did not affect levels of surface expression of alphaIIbbeta3 nor did it modulate the affinity of an alphaIIbbeta3 mutant that is defective in binding to beta3-endonexin. Affinity modulation of alphaIIbbeta3 by GFP/beta3-endonexin was inhibited by coexpression of either a monomeric beta3 cytoplasmic tail chimera or an activated form of H-Ras. These results demonstrate that beta3-endonexin can modulate the affinity state of alphaIIbbeta3 in a manner that is structurally specific and subject to metabolic regulation. By analogy, the adhesive function of platelets may be regulated by such protein-protein interactions at the level of the cytoplasmic tails of alphaIIbbeta3

Change detection in children with autism: an auditory event-related fMRI study

Autism involves impairments in communication and social interaction, as well as high levels of repetitive, stereotypic and ritualistic behaviours, and extreme resistance to change. This latter dimension, whilst required for a diagnosis, has received less research attention. We hypothesise that this extreme resistance to change in autism is rooted in atypical processing of unexpected stimuli. We tested this using auditory event-related fMRI to determine regional brain activity associated with passive detection of infrequently occurring frequency-deviant and complex novel sounds in a no-task condition. Participants were twelve 10 to 15-year-old children with autism, and a group of 12 age- and sex-matched healthy controls

Predictive Top-Down Integration of Prior Knowledge during Speech Perception

A striking feature of human perception is that our subjective experience depends not only on sensory information from the environment but also on our prior knowledge or expectations. The precise mechanisms by which sensory information and prior knowledge are integrated remain unclear, with longstanding disagreement concerning whether integration is strictly feedforward or whether higher-level knowledge influences sensory processing through feedback connections. Here we used concurrent EEG and MEG recordings to determine how sensory information and prior knowledge are integrated in the brain during speech perception. We manipulated listeners' prior knowledge of speech content by presenting matching, mismatching, or neutral written text before a degraded (noise-vocoded) spoken word. When speech conformed to prior knowledge, subjective perceptual clarity was enhanced. This enhancement in clarity was associated with a spatiotemporal profile of brain activity uniquely consistent with a feedback process: activity in the inferior frontal gyrus was modulated by prior knowledge before activity in lower-level sensory regions of the superior temporal gyrus. In parallel, we parametrically varied the level of speech degradation, and therefore the amount of sensory detail, so that changes in neural responses attributable to sensory information and prior knowledge could be directly compared. Although sensory detail and prior knowledge both enhanced speech clarity, they had an opposite influence on the evoked response in the superior temporal gyrus. We argue that these data are best explained within the framework of predictive coding in which sensory activity is compared with top-down predictions and only unexplained activity propagated through the cortical hierarchy

Listeners and Readers Generalize Their Experience With Word Meanings Across Modalities

Research has shown that adults' lexical-semantic representations are surprisingly malleable. For instance, the interpretation of ambiguous words (e.g., bark) is influenced by experience such that recently encountered meanings become more readily available (Rodd et al., 2016, 2013). However, the mechanism underlying this word-meaning priming effect remains unclear, and competing accounts make different predictions about the extent to which information about word meanings that is gained within one modality (e.g., speech) is transferred to the other modality (e.g., reading) to aid comprehension. In two Web-based experiments, ambiguous target words were primed with either written or spoken sentences that biased their interpretation toward a subordinate meaning, or were unprimed. About 20 min after the prime exposure, interpretation of these target words was tested by presenting them in either written or spoken form, using word association (Experiment 1, N = 78) and speeded semantic relatedness decisions (Experiment 2, N = 181). Both experiments replicated the auditory unimodal priming effect shown previously (Rodd et al., 2016, 2013) and revealed significant cross-modal priming: primed meanings were retrieved more frequently and swiftly across all primed conditions compared with the unprimed baseline. Furthermore, there were no reliable differences in priming levels between unimodal and cross-modal prime-test conditions. These results indicate that recent experience with ambiguous word meanings can bias the reader's or listener's later interpretation of these words in a modality-general way. We identify possible loci of this effect within the context of models of long-term priming and ambiguity resolution

How to study spoken language understanding: a survey of neuroscientific methods

The past 20 years have seen a methodological revolution in spoken language research. A diverse range of neuroscientific techniques are now available that allow researchers to observe the brain’s responses to different types of speech stimuli in both healthy and impaired listeners, and also to observe how individuals’ abilities to process speech change as a consequence of disrupting processing in specific brain regions. This special issue provides a tutorial review of the most important of these methods to guide researchers to make informed choices about which methods are best suited to addressing specific questions concerning the neuro-computational foundations of spoken language understanding. This introductory review provides (i) an historical overview of the experimental study of spoken language understanding, (ii) a summary of the key method currently being used by cognitive neuroscientists in this field, and (iii) thoughts on the likely future developments of these methods

Commentary: Providing Versus Packaging Support for Bereaved Parents After Perinatal Loss

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73421/1/j.1523-536X.1992.tb00384.x.pd

Comparing and Validating Methods of Reading Instruction Using Behavioural and Neural Findings in an Artificial Orthography

There is strong scientific consensus that emphasizing print-to-sound relationships is critical when learning to read alphabetic languages. Nevertheless, reading instruction varies across English-speaking countries, from intensive phonic training to multicuing environments that teach sound- and meaning-based strategies. We sought to understand the behavioral and neural consequences of these differences in relative emphasis. We taught 24 English-speaking adults to read 2 sets of 24 novel words (e.g., /buv/, /sig/), written in 2 different unfamiliar orthographies. Following pretraining on oral vocabulary, participants learned to read the novel words over 8 days. Training in 1 language was biased toward print-to-sound mappings while training in the other language was biased toward print-to-meaning mappings. Results showed striking benefits of print–sound training on reading aloud, generalization, and comprehension of single words. Univariate analyses of fMRI data collected at the end of training showed that print–meaning relative to print–sound relative training increased neural effort in dorsal pathway regions involved in reading aloud. Conversely, activity in ventral pathway brain regions involved in reading comprehension was no different following print–meaning versus print–sound training. Multivariate analyses validated our artificial language approach, showing high similarity between the spatial distribution of fMRI activity during artificial and English word reading. Our results suggest that early literacy education should focus on the systematicities present in print-to-sound relationships in alphabetic languages, rather than teaching meaning-based strategies, in order to enhance both reading aloud and comprehension of written words

Learning and retrieving holistic and componential visual-verbal associations in reading and object naming

Understanding the neural processes that underlie learning to read can provide a scientific foundation for literacy education but studying these processes in real-world contexts remains challenging. We present behavioural data from adult participants learning to read artificial words and name artificial objects over two days. Learning profiles and generalisation confirmed that componential learning of visual-verbal associations distinguishes reading from object naming. Functional MRI data collected on the second day allowed us to identify the neural systems that support componential reading as distinct from systems supporting holistic visual-verbal associations in object naming. Results showed increased activation in posterior ventral occipitotemporal (vOT), parietal, and frontal cortices when reading an artificial orthography compared to naming artificial objects, and the reverse profile in anterior vOT regions. However, activation differences between trained and untrained words were absent, suggesting a lack of cortical representations for whole words. Despite this, hippocampal responses provided some evidence for overnight consolidation of both words and objects learned on day 1. The comparison between neural activity for artificial words and objects showed extensive overlap with systems differentially engaged for real object naming and English word/pseudoword reading in the same participants. These findings therefore provide evidence that artificial learning paradigms offer an alternative method for studying the neural systems supporting language and literacy. Implications for literacy acquisition are discussed

Ocean zoning within a sparing versus sharing framework

The land-sparing versus land-sharing debate centers around how different intensities of habitat use can be coordinated to satisfy competing demands for biodiversity persistence and food production in agricultural landscapes. We apply the broad concepts from this debate to the sea and propose it as a framework to inform marine zoning based on three possible management strategies, establishing: no-take marine reserves, regulated fishing zones, and unregulated open-access areas. We develop a general model that maximizes standing fish biomass, given a fixed management budget while maintaining a minimum harvest level. We find that when management budgets are small, sea-sparing is the optimal management strategy because for all parameters tested, reserves are more cost-effective at increasing standing biomass than traditional fisheries management. For larger budgets, the optimal strategy switches to sea-sharing because, at a certain point, further investing to grow the no-take marine reserves reduces catch below the minimum harvest constraint. Our intention is to illustrate how general rules of thumb derived from plausible, single-purpose models can help guide marine protected area policy under our novel sparing and sharing framework. This work is the beginning of a basic theory for optimal zoning allocations and should be considered complementary to the more specific spatial planning literature for marine reserve as nations expand their marine protected area estates