Child-Oriented Word Associations Improve Models Of Early Word Learning

How words are associated within the linguistic environment conveys semantic content; however, different contexts induce different linguistic patterns. For instance, it is well known that adults speak differently to children than to other adults. We present results from a new word association study in which adult participants were instructed to produce either unconstrained or child-oriented responses to each cue, where cues included 672 nouns, verbs, adjectives, and other word forms from the McArthur-Bates Communicative Development Inventory (CDI; Fenson et al., 2006). Child-oriented responses consisted of higher frequency words with fewer letters, earlier ages of acquisition, and higher contextual diversity. Furthermore, the correlations among the responses generated for each pair of cues differed between unconstrained (adult-oriented) and child-oriented responses, suggesting that child-oriented associations imply different semantic structure. A comparison of growth models guided by a semantic network structure revealed that child-oriented associations are more predictive of early lexical growth. Additionally, relative to a growth model based on a corpus of naturalistic child-directed speech, the child-oriented associations explain added unique variance to lexical growth. Thus, these new child-oriented word association norms provide novel insight into the semantic context of young children and early lexical development

Characterizing the early vocabulary profiles of preverbal and minimally verbal children with autism spectrum disorder

Abstract Children with autism spectrum disorder (ASD) often have significant language delays. But do they learn language differently than neurotypical toddlers? We compared the lexical skills of 64 preverbal and minimally verbal children with ASD, to 461 vocabulary-size-matched typically developing (TD) toddlers. We also examined social features of verb knowledge using a novel collection of social ratings. Children with ASD produced proportionally more verbs than TD toddlers. Children with ASD produced proportionally more action and food words, while TD toddlers produced proportionally more animal, people words, and animal sounds and sound effects. Children with ASD also produced “mommy” and “daddy” at lower rates. We discuss how these differences may reflect an association between lexical development and weaknesses in social communication. Lay abstract Although preverbal and minimally verbal (PV-MV) children with autism spectrum disorder (ASD) represent a significant portion of the ASD population, we have a limited understanding of and characterization of them. Though it is a given that their lexical profiles contain fewer words, it is important to determine whether: a) the words PV-MV children with ASD produce are similar to the first words typically developing (TD) children produce, or b) there are unique features of the limited words that PV-MV children with ASD produce. The current study compared the early word profiles of PV-MV children with ASD to vocabulary-matched TD toddlers. Children with ASD produced proportionally more verbs than TD toddlers. Also, children with ASD produced proportionally more action and food words, while TD toddlers produced proportionally more animal words, animal sounds and sound effects, and people words. Children with ASD also produced “mommy” and “daddy” at lower rates. Our findings identified several areas of overlap in early word learning; however, our findings also point to differences that may be connected to core weaknesses in social communication (i.e., people words). The findings highlight words and categories that could serve as useful targets for communication intervention with PV-MV children with ASD

ARHGEF7 (BETA-PIX) Acts as Guanine Nucleotide Exchange Factor for Leucine-Rich Repeat Kinase 2

Background: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial and sporadic Parkinson’s disease. The multidomain protein LRRK2 exhibits overall low GTPase and kinase activity in vitro. Methodology/Principal Findings: Here, we show that the rho guanine nucleotide exchange factor ARHGEF7 and the small GTPase CDC42 are interacting with LRRK2 in vitro and in vivo. GTPase activity of full-length LRRK2 increases in the presence of recombinant ARHGEF7. Interestingly, LRRK2 phosphorylates ARHGEF7 in vitro at previously unknown phosphorylation sites. We provide evidence that ARHGEF7 might act as a guanine nucleotide exchange factor for LRRK2 and that R1441C mutant LRRK2 with reduced GTP hydrolysis activity also shows reduced binding to ARHGEF7. Conclusions/Significance: Downstream effects of phosphorylation of ARHGEF7 through LRRK2 could be (i) a feedback control mechanism for LRRK2 activity as well as (ii) an impact of LRRK2 on actin cytoskeleton regulation. A newly identified familial mutation N1437S, localized within the GTPase domain of LRRK2, further underlines the importance of the GTPas

GTPase Activity and Neuronal Toxicity of Parkinson's Disease–Associated LRRK2 Is Regulated by ArfGAP1

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 encodes a large multi-domain protein with GTPase and kinase activity. Initial data indicates that an intact functional GTPase domain is critically required for LRRK2 kinase activity. PD–associated mutations in LRRK2, including the most common G2019S variant, have variable effects on enzymatic activity but commonly alter neuronal process morphology. The mechanisms underlying the intrinsic and extrinsic regulation of LRRK2 GTPase and kinase activity, and the pathogenic effects of familial mutations, are incompletely understood. Here, we identify a novel functional interaction between LRRK2 and ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1). LRRK2 and ArfGAP1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at Golgi membranes. PD–associated and functional mutations that alter the GTPase activity of LRRK2 modulate the interaction with ArfGAP1. The GTP hydrolysis activity of LRRK2 is markedly enhanced by ArfGAP1 supporting a role for ArfGAP1 as a GTPase-activating protein for LRRK2. Unexpectedly, ArfGAP1 promotes the kinase activity of LRRK2 suggesting a potential role for GTP hydrolysis in kinase activation. Furthermore, LRRK2 robustly and directly phosphorylates ArfGAP1 in vitro. Silencing of ArfGAP1 expression in primary cortical neurons rescues the neurite shortening phenotype induced by G2019S LRRK2 overexpression, whereas the co-expression of ArfGAP1 and LRRK2 synergistically promotes neurite shortening in a manner dependent upon LRRK2 GTPase activity. Neurite shortening induced by ArfGAP1 overexpression is also attenuated by silencing of LRRK2. Our data reveal a novel role for ArfGAP1 in regulating the GTPase activity and neuronal toxicity of LRRK2; reciprocally, LRRK2 phosphorylates ArfGAP1 and is required for ArfGAP1 neuronal toxicity. ArfGAP1 may represent a promising target for interfering with LRRK2-dependent neurodegeneration in familial and sporadic PD

LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same

Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places

Interpretations of meaningful and ambiguous hand gestures from individuals with and without Autism Spectrum Disorder (ASD)

Previous research indicates that Autism Spectrum Disorder (ASD) is associated with altered production of co-speech gestures. However, little research has examined whether ASD impacts the processes involved in interpreting observed gestures. We collected meaningfulness ratings and one-word interpretations for 165 video-recorded gestures of varying ambiguity from individuals with and without an ASD diagnosis. The resulting dataset contains insights into gesture processing in individuals with and without ASD, including the number and variability of interpretations assigned to gestures as well as tendencies to endorse ambiguous gestures as meaningful. We also used a subset of these stimuli to identify the neural mechanisms by which gestures enhance memory in neurotypical adults. This collection of videos, as well as the interpretations and ratings from each group, will be made available through the Open Science Framework for use in future research