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1.  The Broader Autism Phenotype in Infancy: When Does It Emerge? 
Objective
This study had three goals, to examine: 1) the frequency of atypical development, consistent with the broader autism phenotype, in high-risk infant siblings of children with ASD, 2) the age at which atypical development is first evident, and 3) which developmental domains are affected.
Method
A prospective longitudinal design was used to compare 294 high-risk infants and 116 low-risk infants. Participants were tested at 6, 12, 18, 24, and 36 months of age. At the final visit, outcome was classified as ASD, Typical Development (TD), or Non-TD (defined as elevated ADOS score, low Mullen scores, or both).
Results
28% of the high-risk group was classified as Non-TD at 36 months of age. Growth curve models demonstrated that the Non-TD group could not be distinguished from the other groups at 6 months of age, but differed significantly from the Low-Risk TD group by 12 months on multiple measures. The Non-TD group demonstrated atypical development in cognitive, motor, language, and social domains, with differences particularly prominent in social-communication.
Conclusions
These results demonstrate that features of atypical development, consistent with the broader autism phenotype, are detectable by the first birthday and affect development in multiple domains. This highlights the necessity for close developmental surveillance of infant siblings of children with ASD, along with implementation of appropriate interventions as needed.
doi:10.1016/j.jaac.2013.12.020
PMCID: PMC3989934  PMID: 24655649
Autism Spectrum Disorder; broader autism phenotype; siblings; social-communication; infancy
2.  Efficacy of a Parainfluenza Virus 5 (PIV5)-Based H7N9 Vaccine in Mice and Guinea Pigs: Antibody Titer towards HA Was Not a Good Indicator for Protection 
PLoS ONE  2015;10(3):e0120355.
H7N9 has caused fatal infections in humans. A safe and effective vaccine is the best way to prevent large-scale outbreaks in the human population. Parainfluenza virus 5 (PIV5), an avirulent paramyxovirus, is a promising vaccine vector. In this work, we generated a recombinant PIV5 expressing the HA gene of H7N9 (PIV5-H7) and tested its efficacy against infection with influenza virus A/Anhui/1/2013 (H7N9) in mice and guinea pigs. PIV5-H7 protected the mice against lethal H7N9 challenge. Interestingly, the protection did not require antibody since PIV5-H7 protected JhD mice that do not produce antibody against lethal H7N9 challenge. Furthermore, transfer of anti-H7 serum did not protect mice against H7N9 challenge. PIV5-H7 generated high HAI titers in guinea pigs, however it did not protect against H7N9 infection or transmission. Intriguingly, immunization of guinea pigs with PIV5-H7 and PIV5 expressing NP of influenza A virus H5N1 (PIV5-NP) conferred protection against H7N9 infection and transmission. Thus, we have obtained a H7N9 vaccine that protected both mice and guinea pigs against lethal H7N9 challenge and infection respectively.
doi:10.1371/journal.pone.0120355
PMCID: PMC4372596  PMID: 25803697
4.  Multiplexed screening of natural humoral immunity identifies antibodies at fine specificity for complex and dynamic viral targets 
mAbs  2014;6(2):460-473.
Viral entry targets with therapeutic neutralizing potential are subject to multiple escape mechanisms, including antigenic drift, immune dominance of functionally irrelevant epitopes, and subtle variations in host cell mechanisms. A surprising finding of recent years is that potent neutralizing antibodies to viral epitopes independent of strain exist, but are poorly represented across the diverse human population. Identifying these antibodies and understanding the biology mediating the specific immune response is thus difficult. An effective strategy for meeting this challenge is to incorporate multiplexed antigen screening into a high throughput survey of the memory B cell repertoire from immune individuals. We used this approach to discover suites of cross-clade antibodies directed to conformational epitopes in the stalk region of the influenza A hemagglutinin (HA) protein and to select high-affinity anti-peptide antibodies to the glycoprotein B (gB) of human cytomegalovirus. In each case, our screens revealed a restricted VH and VL germline usage, including published and previously unidentified gene families. The in vivo evolution of paratope specificity with optimal neutralizing activity was understandable after correlating biological activities with kinetic binding and epitope recognition. Iterative feedback between antigen probe design based on structure and function information with high throughput multiplexed screening demonstrated a generally applicable strategy for efficient identification of safe, native, finely tuned antibodies with the potential for high genetic barriers to viral escape.
doi:10.4161/mabs.27760
PMCID: PMC3984334  PMID: 24492306
monoclonal antibodies; human antibodies; neutralizing antibodies; broadly protective antibodies; immunoglobulin germline; viral epitopes; fusion; influenza; cytomegalovirus
5.  Verdinexor, a Novel Selective Inhibitor of Nuclear Export, Reduces Influenza A Virus Replication In Vitro and In Vivo 
Journal of Virology  2014;88(17):10228-10243.
ABSTRACT
Influenza is a global health concern, causing death, morbidity, and economic losses. Chemotherapeutics that target influenza virus are available; however, rapid emergence of drug-resistant strains is common. Therapeutic targeting of host proteins hijacked by influenza virus to facilitate replication is an antiviral strategy to reduce the development of drug resistance. Nuclear export of influenza virus ribonucleoprotein (vRNP) from infected cells has been shown to be mediated by exportin 1 (XPO1) interaction with viral nuclear export protein tethered to vRNP. RNA interference screening has identified XPO1 as a host proinfluenza factor where XPO1 silencing results in reduced influenza virus replication. The Streptomyces metabolite XPO1 inhibitor leptomycin B (LMB) has been shown to limit influenza virus replication in vitro; however, LMB is toxic in vivo, which makes it unsuitable for therapeutic use. In this study, we tested the anti-influenza virus activity of a new class of orally available small-molecule selective inhibitors of nuclear export, specifically, the XPO1 antagonist KPT-335 (verdinexor). Verdinexor was shown to potently and selectively inhibit vRNP export and effectively inhibited the replication of various influenza virus A and B strains in vitro, including pandemic H1N1 virus, highly pathogenic H5N1 avian influenza virus, and the recently emerged H7N9 strain. In vivo, prophylactic and therapeutic administration of verdinexor protected mice against disease pathology following a challenge with influenza virus A/California/04/09 or A/Philippines/2/82-X79, as well as reduced lung viral loads and proinflammatory cytokine expression, while having minimal toxicity. These studies show that verdinexor acts as a novel anti-influenza virus therapeutic agent.
IMPORTANCE Antiviral drugs represent important means of influenza virus control. However, substantial resistance to currently approved influenza therapeutic drugs has developed. New antiviral approaches are required to address drug resistance and reduce the burden of influenza virus-related disease. This study addressed critical preclinical studies for the development of verdinexor (KPT-335) as a novel antiviral drug. Verdinexor blocks progeny influenza virus genome nuclear export, thus effectively inhibiting virus replication. Verdinexor was found to limit the replication of various strains of influenza A and B viruses, including a pandemic H1N1 influenza virus strain, a highly pathogenic H5N1 avian influenza virus strain, and a recently emerging H7N9 influenza virus strain. Importantly, oral verdinexor treatments, given prophylactically or therapeutically, were efficacious in limiting lung virus burdens in influenza virus-infected mice, in addition to limiting lung proinflammatory cytokine expression, pathology, and death. Thus, this study demonstrated that verdinexor is efficacious against influenza virus infection in vitro and in vivo.
doi:10.1128/JVI.01774-14
PMCID: PMC4136318  PMID: 24965445
6.  Polypropylene Surgical Mesh Coated with Extracellular Matrix Mitigates the Host Foreign Body Response 
Surgical mesh devices composed of synthetic materials are commonly used for ventral hernia repair. These materials provide robust mechanical strength and are quickly incorporated into host tissue; factors which contribute to reduced hernia recurrence rates. However, such mesh devices cause a foreign body response with the associated complications of fibrosis and patient discomfort. In contrast, surgical mesh devices composed of naturally occurring extracellular matrix (ECM) are associated with constructive tissue remodeling, but lack the mechanical strength of synthetic materials. A method for applying a porcine dermal ECM hydrogel coating to a polypropylene mesh is described herein with the associated effects upon the host tissue response and biaxial mechanical behavior. Uncoated and ECM coated heavy-weight BARD™ Mesh were compared to the light-weight ULTRAPRO™ and BARD™ Soft Mesh devices in a rat partial thickness abdominal defect overlay model. The ECM coated mesh attenuated the pro-inflammatory response compared to all other devices, with a reduced cell accumulation and fewer foreign body giant cells. The ECM coating degraded by 35 days, and was replaced with loose connective tissue compared to the dense collagenous tissue associated with the uncoated polypropylene mesh device. Biaxial mechanical characterization showed that all of the mesh devices were of similar isotropic stiffness. Upon explantation, the light-weight mesh devices were more compliant than the coated or uncoated heavy-weight devices. The present study shows that an ECM coating alters the default host response to a polypropylene mesh, but not the mechanical properties in an acute in vivo abdominal repair model.
doi:10.1002/jbm.a.34671
PMCID: PMC3808505  PMID: 23873846
Extracellular Matrix (ECM); polypropylene; surgical mesh; coated surgical mesh; foreign body response
7.  Does bilingual experience affect early visual perceptual development? 
Frontiers in Psychology  2014;5:1429.
Visual attention and perception develop rapidly during the first few months after birth, and these behaviors are critical components in the development of language and cognitive abilities. Here we ask how early bilingual experiences might lead to differences in visual attention and perception. Experiments 1–3 investigated the looking behavior of monolingual and bilingual infants when presented with social (Experiment 1), mixed (Experiment 2), or non-social (Experiment 3) stimuli. In each of these experiments, infants' dwell times (DT) and number of fixations to areas of interest (AOIs) were analyzed, giving a sense of where the infants looked. To examine how the infants looked at the stimuli in a more global sense, Experiment 4 combined and analyzed the saccade data collected in Experiments 1–3. There were no significant differences between monolingual and bilingual infants' DTs, AOI fixations, or saccade characteristics (specifically, frequency, and amplitude) in any of the experiments. These results suggest that monolingual and bilingual infants process their visual environments similarly, supporting the idea that the substantial cognitive differences between monolinguals and bilinguals in early childhood are more related to active vocabulary production than perception of the environment.
doi:10.3389/fpsyg.2014.01429
PMCID: PMC4263081  PMID: 25566116
bilingualism; language; cognition; perception; infancy; development
8.  Amino acid-mediated impacts of elevated carbon dioxide and simulated root herbivory on aphids are neutralized by increased air temperatures 
Journal of Experimental Botany  2014;66(2):613-623.
Highlight
Multiple abiotic factors can combine to alter crop quality and rates of herbivore attack. Aphids benefit from elevated CO2 and root damage, but these effects are neutralized by increased temperatures.
Changes in host plant quality, including foliar amino acid concentrations, resulting from global climate change and attack from multiple herbivores, have the potential to modify the pest status of insect herbivores. This study investigated how mechanically simulated root herbivory of lucerne (Medicago sativa) before and after aphid infestation affected the pea aphid (Acyrthosiphon pisum) under elevated temperature (eT) and carbon dioxide concentrations (eCO2). eT increased plant height and biomass, and eCO2 decreased root C:N. Foliar amino acid concentrations and aphid numbers increased in response to eCO2, but only at ambient temperatures, demonstrating the ability of eT to negate the effects of eCO2. Root damage reduced aboveground biomass, height, and root %N, and increased root %C and C:N, most probably via decreased biological nitrogen fixation. Total foliar amino acid concentrations and aphid colonization success were higher in plants with roots cut early (before aphid arrival) than those with roots cut late (after aphid arrival); however, this effect was counteracted by eT. These results demonstrate the importance of amino acid concentrations for aphids and identify individual amino acids as being potential factors underpinning aphid responses to eT, eCO2, and root damage in lucerne. Incorporating trophic complexity and multiple climatic factors into plant–herbivore studies enables greater insight into how plants and insects will interact in the future, with implications for sustainable pest control and future crop security.
doi:10.1093/jxb/eru439
PMCID: PMC4286407  PMID: 25403916
Aboveground–belowground interactions; aphid; climate change; legume; root herbivore; simulated herbivory.
9.  Reciprocal feeding facilitation between above- and below-ground herbivores 
Biology Letters  2013;9(5):20130341.
Interspecific interactions between insect herbivores predominantly involve asymmetric competition. By contrast, facilitation, whereby herbivory by one insect benefits another via induced plant susceptibility, is uncommon. Positive reciprocal interactions between insect herbivores are even rarer. Here, we reveal a novel case of reciprocal feeding facilitation between above-ground aphids (Amphorophora idaei) and root-feeding vine weevil larvae (Otiorhynchus sulcatus), attacking red raspberry (Rubus idaeus). Using two raspberry cultivars with varying resistance to these herbivores, we further demonstrate that feeding facilitation occurred regardless of host plant resistance. This positive reciprocal interaction operates via an, as yet, unreported mechanism. Specifically, the aphid induces compensatory growth, possibly as a prelude to greater resistance/tolerance, whereas the root herbivore causes the plant to abandon this strategy. Both herbivores may ultimately benefit from this facilitative interaction.
doi:10.1098/rsbl.2013.0341
PMCID: PMC3971671  PMID: 23883576
interspecific competition; plant–insect interactions; Otiorhynchus sulcatus; Amphorophora idaei
10.  Sex-related preferences for real and doll’s faces versus real and toy objects in young infants and adults 
Findings of previous studies demonstrate sex-related preferences for toys in 6-month-old infants: Boys prefer non-social or mechanical toys such as cars, while girls prefer social toys such as dolls. Here, we explored the innate versus learned nature of this sex-related preferences using multiple pictures of doll and real faces (of men and women) as well as pictures of toy and real objects (cars and stoves). Forty-eight 4- and 5-month-old infants (24 girls) and 48 young adults (24 women) saw six trials of all relevant pairs of faces and objects, with each trial containing a different exemplar of a stimulus type. The infant results showed no sex-related preferences; infants preferred faces of men and women, regardless of whether they were real or doll’s faces. Similarly, adults did not show sex-related preferences for social versus non-social stimuli, but, unlike infants, they preferred faces of the opposite sex over objects. These results challenge claims of an innate basis for sex-related preferences for toy and real stimuli preferences (Connellan et al., 2000) and suggest that sex-related preferences result from maturational and social development, which continues into adulthood.
doi:10.1016/j.jecp.2013.07.001
PMCID: PMC3766397  PMID: 23933180
11.  Perfusion-decellularized pancreas as a natural 3D scaffold for pancreatic tissue and whole organ engineering 
Biomaterials  2013;34(28):6760-6772.
Approximately 285 million people worldwide suffer from diabetes, with insulin supplementation as the most common treatment measure. Regenerative medicine approaches such as a bioengineered pancreas has been proposed as potential therapeutic alternatives. A bioengineered pancreas will benefit from the development of a bioscaffold that supports and enhances cellular function and tissue development. Perfusion-decellularized organs are a likely candidate for use in such scaffolds since they mimic compositional, architectural and biomechanical nature of a native organ. In this study, we investigate perfusion-decellularization of whole pancreas and the feasibility to recellularize the whole pancreas scaffold with pancreatic cell types. Our result demonstrates that perfusion-decellularization of whole pancreas effectively removes cellular and nuclear material while retaining intricate three-dimensional microarchitecture with perfusable vasculature and ductal network and crucial extracellular matrix (ECM) components. To mimic pancreatic cell composition, we recellularized the whole pancreas scaffold with acinar and beta cell lines and cultured up to 5 days. Our result shows successful cellular engraftment within the decellularized pancreas, and the resulting graft gave rise to strong up-regulation of insulin gene expression. These findings support biological utility of whole pancreas ECM as a biomaterials scaffold for supporting and enhancing pancreatic cell functionality and represent a step toward bioengineered pancreas using regenerative medicine approaches.
doi:10.1016/j.biomaterials.2013.05.066
PMCID: PMC3748589  PMID: 23787110
Whole organ decellularization; Extracellular matrix scaffold; Tissue and organ engineering; Pancreatic β-cells
12.  Relationship of Adipokines with Immune Response and Lung Function in Obese Asthmatic and Non-Asthmatic Women 
Background
Obesity is a risk factor for asthma. Studies in mice suggest that the adipokines leptin and adiponectin affect asthmatic responses. The purpose of this study was to determine if adipokines associated with obesity are (1) altered in obese women with asthma compared to controls and (2) associated with increased cytokines and chemokines involved in allergic inflammation.
Methods
We performed a cross-sectional study of asthmatic and non-asthmatic obese premenopausal women. Participants answered questionnaires and performed lung function tests. Serum and peripheral blood mononuclear cells (PBMCs) were collected for analysis of cytokines and adipokines.
Results
A total of 22 asthmatic (mean body mass index 40.0 ± 5.1 kg/m) and 20 non-asthmatic women (mean body mass index 41.3 ± 5.6 kg/m2) participated. We found no difference in serum adipokine concentrations between asthmatics and non-asthmatics. Serum adiponectin correlated positively with PBMC eotaxin (rs = 0.55, p = .0003) and RANTES (regulated upon activation, normal T-cell expressed, and secreted) (rs = 0.36, p = .03), whereas serum leptin correlated negatively with PBMC eotaxin (rs = −0.34, p = .04). There was a negative correlation between serum adiponectin and PBMC interferon-γ (rs = −0.41, p = .01).
Conclusions
Perturbations of adipokines that occur in obesity were correlated with decreased cytokine production typically associated with allergic responses in PBMC of obese premenopausal women. This study suggests that although obese asthmatics may have elements of Th2-mediated inflammation, adipokine derangements in obesity are associated with Th1 rather than Th2 bias. Obesity has complex effects on allergic inflammation and is likely to be important modifier of the pathogenesis of airway disease in asthma.
doi:10.3109/02770903.2011.613507
PMCID: PMC4133269  PMID: 21942353
asthma; inflammation; obesity; Th1/Th2
13.  Novel H7N9 Influenza Virus Shows Low Infectious Dose, High Growth Rate, and Efficient Contact Transmission in the Guinea Pig Model 
Journal of Virology  2014;88(3):1502-1512.
The zoonotic outbreak of H7N9 subtype avian influenza virus that occurred in eastern China in the spring of 2013 resulted in 135 confirmed human cases, 44 of which were lethal. Sequencing of the viral genome revealed a number of molecular signatures associated with virulence or transmission in mammals. We report here that, in the guinea pig model, a human isolate of novel H7N9 influenza virus, A/Anhui/1/2013 (An/13), is highly dissimilar to an H7N1 avian isolate and instead behaves similarly to a human seasonal strain in several respects. An/13 was found to have a low 50% infectious dose, grow to high titers in the upper respiratory tract, and transmit efficiently among cocaged guinea pigs. The pH of fusion of the hemagglutinin (HA) and the binding of virus to fixed guinea pig tissues were also examined. The An/13 HA displayed a relatively elevated pH of fusion characteristic of many avian strains, and An/13 resembled avian viruses in terms of attachment to tissues. One important difference was seen between An/13 and both the H3N2 human and the H7N1 avian viruses: when inoculated intranasally at a high dose, only the An/13 virus led to productive infection of the lower respiratory tract of guinea pigs. In sum, An/13 was found to retain fusion and attachment properties of an avian influenza virus but displayed robust growth and contact transmission in the guinea pig model atypical of avian strains and indicative of mammalian adaptation.
doi:10.1128/JVI.02959-13
PMCID: PMC3911619  PMID: 24227867
14.  Molecular signatures of antibody responses derived from a systems biological study of 5 human vaccines 
Nature immunology  2013;15(2):195-204.
Many vaccines induce protective immunity via antibodies. Recent studies have used systems biological approaches to determine signatures that predict vaccine immunity in humans, but whether there is a ‘universal signature’ that can predict antibody responses to any vaccine, is unknown. Here we performed systems analyses of immune responses to the meningococcal polysaccharide and conjugate vaccines in healthy adults, in the broader context of our previous studies with the yellow fever and two influenza vaccines. To achieve this, we performed a large-scale network integration of public human blood transcriptomes, and systems-scale databases in specific biological contexts, and deduced a set of blood transcription modules. These modules revealed distinct transcriptional signatures of antibody responses to different classes of vaccines providing key insights into primary viral, protein recall and anti-polysaccharide responses. These results illuminate the early transcriptional programs orchestrating vaccine immunity in humans, and demonstrate the power of integrative network modeling.
doi:10.1038/ni.2789
PMCID: PMC3946932  PMID: 24336226
15.  Simulating the role of visual selective attention during the development of perceptual completion 
Developmental science  2012;15(6):739-752.
We recently proposed a multi-channel, image-filtering model for simulating the development of visual selective attention in young infants (Schlesinger, Amso & Johnson, 2007). The model not only captures the performance of 3-month-olds on a visual search task, but also implicates two cortical regions that may play a role in the development of visual selective attention. In the current simulation study, we used the same model to simulate 3-month-olds’ performance on a second measure, the perceptual unity task. Two parameters in the model – corresponding to areas in the occipital and parietal cortices – were systematically varied while the gaze patterns produced by the model were recorded and subsequently analyzed. Three key findings emerged from the simulation study. First, the model successfully replicated the performance of 3-month-olds on the unity perception task. Second, the model also helps to explain the improved performance of 2-month-olds when the size of the occluder in the unity perception task is reduced. Third, in contrast to our previous simulation results, variation in only one of the two cortical regions simulated (i.e. recurrent activity in posterior parietal cortex) resulted in a performance pattern that matched 3-month-olds. These findings provide additional support for our hypothesis that the development of perceptual completion in early infancy is promoted by progressive improvements in visual selective attention and oculomotor skill.
doi:10.1111/j.1467-7687.2012.01177.x
PMCID: PMC4101467  PMID: 23106728
16.  Memory constraints on infants’ cross-situational statistical learning 
Cognition  2013;127(3):375-382.
Infants are able to map linguistic labels to referents in the world by tracking co-occurrence probabilities across learning events, a behavior often termed cross-situational statistical learning. This study builds upon existing research by examining infants’ developing ability to aggregate and retrieve word-referent pairings over time. 16- and 20-month-old infants (N = 32) were presented with a cross-situational statistical learning task in which half of the object-label pairings were presented in immediate succession (massed) and half were distributed across time (interleaved). Results revealed striking developmental differences in word mapping performance; infants in both age groups were able to learn pairings presented in immediate succession, but only 20-month-old infants were able to correctly infer pairings distributed over time. This work reveals significant constraints on infants’ ability to aggregate and retrieve object-label pairings across time and challenges theories of cross-situational statistical learning that rest on retrieval processes as successful and automatic.
doi:10.1016/j.cognition.2013.02.015
PMCID: PMC4099971  PMID: 23545387
Cross-situational learning; Statistical learning; Word mapping; Language development; Memory development
17.  Sound support: Intermodal information facilitates infants’ perception of an occluded trajectory 
Infant behavior & development  2011;35(1):174-178.
In a visual occlusion task, 4-month-olds were given a dynamic sound cue (following the trajectory of an object), or a static cue (sound remained stationary). Infants’ oculomotor anticipations were greater in the Dynamic condition, suggesting that representations of visual occlusion were supported by auditory information.
doi:10.1016/j.infbeh.2011.09.001
PMCID: PMC4085162  PMID: 22030100
Multimodal; Infancy; Object trajectory; Eye tracking; Intermodal; Perception
18.  Trajectory Perception and Object Continuity: Effects of Shape and Color Change on 4-Month-Olds’ Perception of Object Identity 
Developmental psychology  2012;49(6):1021-1026.
Previous work has demonstrated that infants use object trajectory continuity as a cue to the constant identity of an object, but results are equivocal regarding the role of object features, with some work suggesting that a change in the appearance of an object does not cue a change in identity. In an experiment involving 72 participants, we investigated the effects of changing object shape and color, singly and in combination, on 4-month-olds’ perception of object continuity. A change in the shape of an object while it passed behind an occluder had no effect on perception of continuity, whereas a change in shape and color led to perception of discontinuity, and a change in color led to no clear percept regarding continuity or discontinuity. These results are discussed in terms of a perceptual learning model of development of object identity.
doi:10.1037/a0029398
PMCID: PMC4085165  PMID: 22799585
trajectory; object identity; shape; color; occlusion
19.  Detecting “Infant-directedness” in Face and Voice 
Developmental science  2014;17(4):621-627.
Five- and 3-month-old infants’ perception of infant-directed (ID) faces and the role of speech in perceiving faces were examined. Infants’ eye movements were recorded as they viewed a series of two side-by-side talking faces, one infant-directed and one adult-directed (AD), while listening to ID speech, AD speech, or in silence. Infants showed consistently greater dwell time on ID faces vs. AD faces, and this ID face preference was consistent across all three sound conditions. ID speech resulted in higher looking overall, but it did not increase looking at the ID face per se. Together, these findings demonstrate that infants’ preferences for ID speech extend to ID faces.
doi:10.1111/desc.12146
PMCID: PMC4069237  PMID: 24576091
face perception; infant-directedness; infant-directed speech
20.  Targeting Cell Division Cycle 25 Homolog B To Regulate Influenza Virus Replication 
Journal of Virology  2013;87(24):13775-13784.
Influenza virus is a worldwide global health concern causing seasonal morbidity mortality and economic burden. Chemotherapeutics is available; however, rapid emergence of drug-resistant influenza virus strains has reduced its efficacy. Thus, there is a need to discover novel antiviral agents. In this study, RNA interference (RNAi) was used to screen host genes required for influenza virus replication. One pro-influenza virus host gene identified was dual-specificity phosphatase cell division cycle 25 B (CDC25B). RNAi screening of CDC25B resulted in reduced influenza A virus replication, and a CDC25B small-molecule inhibitor (NSC95397) inhibited influenza A virus replication in a dose-dependent fashion. Viral RNA synthesis was reduced by NSC95397 in favor of increased beta interferon (IFN-β) expression, and NSC95397 was found to interfere with nuclear localization and chromatin association of NS1, an influenza virus protein. As NS1 has been shown to be chromatin associated and to suppress host transcription, it is likely that CDC25B supports NS1 nuclear function to hijack host transcription machinery in favor of viral RNA synthesis, a process that is blocked by NSC95397. Importantly, NSC95397 treatment protects mice against lethal influenza virus challenge. The findings establish CDC25B as a pro-influenza A virus host factor that may be targeted as a novel influenza A therapeutic strategy.
doi:10.1128/JVI.01509-13
PMCID: PMC3838213  PMID: 24109234
21.  Prediction-learning in infants as a mechanism for gaze control during object exploration 
We are pursuing the hypothesis that visual exploration and learning in young infants is achieved by producing gaze-sample sequences that are sequentially predictable. Our recent analysis of infants’ gaze patterns during image free-viewing (Schlesinger and Amso, 2013) provides support for this idea. In particular, this work demonstrates that infants’ gaze samples are more easily learnable than those produced by adults, as well as those produced by three artificial-observer models. In the current study, we extend these findings to a well-studied object-perception task, by investigating 3-month-olds’ gaze patterns as they view a moving, partially occluded object. We first use infants’ gaze data from this task to produce a set of corresponding center-of-gaze (COG) sequences. Next, we generate two simulated sets of COG samples, from image-saliency and random-gaze models, respectively. Finally, we generate learnability estimates for the three sets of COG samples by presenting each as a training set to an SRN. There are two key findings. First, as predicted, infants’ COG samples from the occluded-object task are learned by a pool of simple recurrent networks faster than the samples produced by the yoked, artificial-observer models. Second, we also find that resetting activity in the recurrent layer increases the network’s prediction errors, which further implicates the presence of temporal structure in infants’ COG sequences. We conclude by relating our findings to the role of image-saliency and prediction-learning during the development of object perception.
doi:10.3389/fpsyg.2014.00441
PMCID: PMC4033257  PMID: 24904460
object perception; prediction-learning; infant development, eye movements; visual saliency
22.  Elevated Atmospheric CO2 Triggers Compensatory Feeding by Root Herbivores on a C3 but Not a C4 Grass 
PLoS ONE  2014;9(3):e90251.
Predicted increases in atmospheric carbon dioxide (CO2) concentrations often reduce nutritional quality for herbivores by increasing the C∶N ratio of plant tissue. This frequently triggers compensatory feeding by aboveground herbivores, whereby they consume more shoot material in an attempt to meet their nutritional needs. Little, however, is known about how root herbivores respond to such changes. Grasslands are particularly vulnerable to root herbivores, which can collectively exceed the mass of mammals grazing aboveground. Here we provide novel evidence for compensatory feeding by a grass root herbivore, Sericesthis nigrolineata, under elevated atmospheric CO2 (600 µmol mol−1) on a C3 (Microlaena stipoides) but not a C4 (Cymbopogon refractus) grass species. At ambient CO2 (400 µmol mol−1) M. stipoides roots were 44% higher in nitrogen (N) and 7% lower in carbon (C) concentrations than C. refractus, with insects performing better on M. stipoides. Elevated CO2 decreased N and increased C∶N in M. stipoides roots, but had no impact on C. refractus roots. Root-feeders displayed compensatory feeding on M. stipoides at elevated CO2, consuming 118% more tissue than at ambient atmospheric CO2. Despite this, root feeder biomass remained depressed by 24%. These results suggest that compensatory feeding under elevated atmospheric CO2 may make some grass species particularly vulnerable to attack, potentially leading to future shifts in the community composition of grasslands.
doi:10.1371/journal.pone.0090251
PMCID: PMC3961222  PMID: 24651855
23.  Infants’ perception of chasing 
Cognition  2012;126(2):224-233.
Two significant questions in cognitive and developmental science are first, whether objects and events are selected for attention based on their features (featural processing) or the configuration of their features (configural processing), and second, how these modes of processing develop. These questions have been addressed in part with experiments focused on infants’ perception of faces, human body shapes, and biological motion of individual agents. Here, we investigate 4- and 10-month-old infants’ (N = 192) attention to social motions, specifically to chasing—a ubiquitous, ancient, and fitness-relevant mode of interaction. We constructed computer-generated animations of chasing that had three properties: acceleration, high turning rates, and attraction (“heat-seeking”). In the first experiment we showed chasing side-by-side with a control display of inanimate, billiard-ball-like motions. Infants strongly preferred attending to chasing. In the next three studies, we systematically investigated the effect of each property in turn (acceleration, turning, and attraction) by showing a display of that property side-by-side with the control display. Infants preferentially attended to acceleration, and to attraction, but not to turning. If infants preferred chasing for its configuration, then the sum of the effect sizes of individual properties should be smaller than their combined effects. That is not what we found: instead, on three measures of visual behavior, the summed effects of individual properties equaled (or exceeded) that of chasing. Moreover, although attraction drew little attention and turning no attention at all, acceleration drew (nearly) as much attention as chasing. Our results thus provide evidence that infants preferred chasing because of its features, not its configuration.
doi:10.1016/j.cognition.2012.10.001
PMCID: PMC3529835  PMID: 23121710
chasing; animate-inanimate distinction; featural and configural processing
24.  Hydrogels Derived from Central Nervous System Extracellular Matrix 
Biomaterials  2012;34(4):1033-1040.
Biologic scaffolds composed of extracellular matrix (ECM) are commonly used repair devices in preclinical and clinical settings; however the use of these scaffolds for peripheral and central nervous system (CNS) repair has been limited. Biologic scaffolds developed from brain and spinal cord tissue have recently been described, yet the conformation of the harvested ECM limits therapeutic utility. An injectable CNS-ECM derived hydrogel capable of in vivo polymerization and conformation to irregular lesion geometries may aid in tissue reconstruction efforts following complex neurologic trauma. The objectives of the present study were to develop hydrogel forms of brain and spinal cord ECM and compare the resulting biochemical composition, mechanical properties, and neurotrophic potential of a brain derived cell line to a non-CNS-ECM hydrogel, urinary bladder matrix. Results showed distinct differences between compositions of brain ECM, spinal cord ECM, and urinary bladder matrix. The rheologic modulus of spinal cord ECM hydrogel was greater than that of brain ECM and urinary bladder matrix. All ECMs increased the number of cells expressing neurites, but only brain ECM increased neurite length, suggesting a possible tissue-specific effect. All hydrogels promoted three-dimensional uni- or bi-polar neurite outgrowth following 7 days in culture. These results suggest that CNS-ECM hydrogels may provide supportive scaffolding to promote in vivo axonal repair.
doi:10.1016/j.biomaterials.2012.10.062
PMCID: PMC3512573  PMID: 23158935
25.  Oculomotor Exploration of Impossible Figures in Early Infancy 
Previous studies with young infants revealed that young infants can distinguish between displays of possible or impossible figures, which may require detection of inconsistent depth relations among local line junctions that disrupt global object configurations. Here, we used an eye-tracking paradigm to record eye movements in young infants during an object discrimination task with matched pairs of possible and impossible figures. Our goal was to identify differential patterns of oculomotor activity as infants viewed pictures of possible and impossible objects. We predicted that infants would actively attend to specific pictorial depth cues that denote shape (e.g., T-junctions), and in the context of an impossible figure that they would fixate to a greater extent in anomalous regions of the display relative to other parts. By the age of 4 months, infants fixated reliably longer overall on displays of impossible vs. possible cubes, specifically within the critical region where the incompatible lines and irreconcilable depth relations were located, implying an early capacity for selective attention to critical line junction information and integration of local depth cues necessary to perceive object coherence.
doi:10.1111/j.1532-7078.2012.00115.x
PMCID: PMC3640614  PMID: 23646001
visual development; eye tracking; pictorial depth cues; cue integration; impossible objects; 3D coherence; object perception in infancy

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