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Estes A.,University of Washington | Zwaigenbaum L.,University of Alberta | Gu H.,University of North Carolina at Chapel Hill | Gu H.,Carolina Institute for Developmental Disabilities | And 15 more authors.
Journal of Neurodevelopmental Disorders | Year: 2015

Background: To delineate the early progression of autism spectrum disorder (ASD) symptoms, this study investigated developmental characteristics of infants at high familial risk for ASD (HR), and infants at low risk (LR). Methods: Participants included 210 HR and 98 LR infants across 4 sites with comparable behavioral data at age 6, 12, and 24 months assessed in the domains of cognitive development (Mullen Scales of Early Learning), adaptive skills (Vineland Adaptive Behavioral Scales), and early behavioral features of ASD (Autism Observation Scale for Infants). Participants evaluated according to the DSM-IV-TR criteria at 24 months and categorized as ASD-positive or ASD-negative were further stratified by empirically derived cutoff scores using the Autism Diagnostic Observation Schedule yielding four groups: HR-ASD-High, HR-ASD-Moderate (HR-ASD-Mod), HR-ASD-Negative (HR-Neg), and LR-ASD-Negative (LR-Neg). Results: The four groups demonstrated different developmental trajectories that became increasingly distinct from 6 to 24 months across all domains. At 6 months, the HR-ASD-High group demonstrated less advanced Gross Motor and Visual Reception skills compared with the LR-Neg group. By 12 months, the HR-ASD-High group demonstrated increased behavioral features of ASD and decreased cognitive and adaptive functioning compared to the HR-Neg and LR-Neg groups. By 24 months, both the HR-ASD-High and HR-ASD-Moderate groups demonstrated differences from the LR- and HR-Neg groups in all domains. Conclusions: These findings reveal atypical sensorimotor development at 6 months of age which is associated with ASD at 24 months in the most severely affected group of infants. Sensorimotor differences precede the unfolding of cognitive and adaptive deficits and behavioral features of autism across the 6- to 24-month interval. The less severely affected group demonstrates later symptom onset, in the second year of life, with initial differences in the social-communication domain. © 2015 Estes et al. Source


Elison J.T.,University of North Carolina at Chapel Hill | Elison J.T.,Carolina Institute for Developmental Disabilities | Sasson N.J.,University of Texas at Dallas | Turner-Brown L.M.,Carolina Institute for Developmental Disabilities | And 2 more authors.
Research in Autism Spectrum Disorders | Year: 2012

Because previous studies of attention in autism spectrum disorders (ASD) have been restricted in age range examined, little is known about how these processes develop over the course of childhood. In this study we examined cross-sectional age effects on patterns of visual attention to social and nonsocial information in 43 typically developing children and 51 children with ASD ranging in age from 2 to 18. Results indicated a sharp increase in visual exploration with age and a decrease in perseverative and detail-focused attention for both groups of children. However, increased age was associated with greater increases in visual exploration for typically developing children than for those children with ASD. The developmental differences were most pronounced for attention to certain nonsocial stimuli as children with ASD demonstrated a disproportionate attentional bias for these stimuli from very early in life. Disproportionate visual attention to certain nonsocial objects relative to social stimuli in ASD spanned from early to late childhood, and thus may represent both an early and a persistent characteristic of the disorder. © 2011 Elsevier Ltd. All rights reserved. Source


Gordon K.R.,University of North Carolina at Chapel Hill | Wang Y.,University of North Carolina at Chapel Hill | Allbritton N.L.,University of North Carolina at Chapel Hill | Taylor A.M.,University of North Carolina at Chapel Hill | Taylor A.M.,Carolina Institute for Developmental Disabilities
Journal of Biomolecular Screening | Year: 2015

High-throughput screening (HTS) on neurons presents unique difficulties because they are postmitotic, limited in supply, and challenging to harvest from animals or generate from stem cells. These limitations have hindered neurological drug discovery, leaving an unmet need to develop cost-effective technology for HTS using neurons. Traditional screening methods use up to 20,000 neurons per well in 384-well plates. To increase throughput, we use "microraft" arrays, consisting of 1600 square, releasable, paramagnetic, polystyrene microelements (microrafts), each providing a culture surface for 500-700 neurons. These microrafts can be detached from the array and transferred to 384-well plates for HTS; however, they must be centered within wells for automated imaging. Here, we developed a magnet array plate, compatible with HTS fluid-handling systems, to center microrafts within wells. We used finite element analysis to select an effective size of the magnets and confirmed that adjacent magnetic fields do not interfere. We then experimentally tested the plate's centering ability and found a centering efficiency of 100%, compared with 4.35% using a flat magnet. We concluded that microrafts could be centered after settling randomly within the well, overcoming friction, and confirmed these results by centering microrafts containing hippocampal neurons cultured for 8 days. © 2015 Society for Laboratory Automation and Screening. Source


Menon S.,University of North Carolina at Chapel Hill | Boyer N.P.,University of North Carolina at Chapel Hill | Winkle C.C.,University of North Carolina at Chapel Hill | McClain L.M.,Massachusetts Institute of Technology | And 6 more authors.
Developmental Cell | Year: 2015

Neuronal growth cone filopodia contain guidance receptors and contribute to axon guidance; however, the mechanism by which the guidance cue netrin increases filopodia density is unknown. Here, we demonstrate that TRIM9, an E3 ubiquitin ligase that localizes to filopodia tips and binds the netrin receptor DCC, interacts with and ubiquitinates the barbed-end polymerase VASP to modulate filopodial stability during netrin-dependent axon guidance. Studies with murine Trim9+/+ and Trim9-/- cortical neurons, along with a non-ubiquitinatable VASP mutant, demonstrate that TRIM9-mediated ubiquitination of VASP reduces VASP filopodial tip localization, VASP dynamics at tips, and filopodial stability. Upon netrin treatment, VASP is deubiquitinated, which promotes VASP tip localization and filopodial stability. Trim9 deletion induces axon guidance defects in vitro and in vivo, whereas a gradient of deubiquitinase inhibition promotes axon turning in vitro. We conclude that a gradient of TRIM9-mediated ubiquitination of VASP creates a filopodial stability gradient during axon turning. © 2015 Elsevier Inc. Source


Kamande J.W.,University of North Carolina at Chapel Hill | Wang Y.,University of North Carolina at Chapel Hill | Taylor A.M.,University of North Carolina at Chapel Hill | Taylor A.M.,Neuroscience Center | Taylor A.M.,Carolina Institute for Developmental Disabilities
Biomicrofluidics | Year: 2015

In recent years, there has been a dramatic increase in the use of poly(dimethylsiloxane) (PDMS) devices for cell-based studies. Commonly, the negative tone photoresist, SU8, is used to pattern features onto silicon wafers to create masters (SU8-Si) for PDMS replica molding. However, the complexity in the fabrication process, low feature reproducibility (master-to-master variability), silane toxicity, and short life span of these masters have been deterrents for using SU8-Si masters for the production of cell culture based PDMS microfluidic devices. While other techniques have demonstrated the ability to generate multiple devices from a single master, they often do not match the high feature resolution (~0.1 μm) and low surface roughness that soft lithography masters offer. In this work, we developed a method to fabricate epoxy-based masters that allows for the replication of features with high fidelity directly from SU8-Si masters via their PDMS replicas. By this method, we show that we could obtain many epoxy based masters with equivalent features to a single SU8-Si master with a low feature variance of 1.54%. Favorable feature transfer resolutions were also obtained by using an appropriate Tg epoxy based system to ensure minimal shrinkage of features ranging in size from ~100 lm to <10 μm in height. We further show that surface coating epoxy masters with Cr/Au lead to effective demolding and yield PDMS chambers that are suitable for long-term culturing of sensitive primary hippocampal neurons. Finally, we incorporated pillars within the Au-epoxy masters to eliminate the process of punching media reservoirs and thereby reducing substantial artefacts and wastage. © 2015 AIP Publishing LLC. Source

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