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1.  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
2.  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
3.  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
4.  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
5.  Root Damage by Insects Reverses the Effects of Elevated Atmospheric CO2 on Eucalypt Seedlings 
PLoS ONE  2013;8(11):e79479.
Predicted increases in atmospheric carbon dioxide (CO2) are widely anticipated to increase biomass accumulation by accelerating rates of photosynthesis in many plant taxa. Little, however, is known about how soil-borne plant antagonists might modify the effects of elevated CO2 (eCO2), with root-feeding insects being particularly understudied. Root damage by insects often reduces rates of photosynthesis by disrupting root function and imposing water deficits. These insects therefore have considerable potential for modifying plant responses to eCO2. We investigated how root damage by a soil-dwelling insect (Xylotrupes gideon australicus) modified the responses of Eucalyptus globulus to eCO2. eCO2 increased plant height when E. globulus were 14 weeks old and continued to do so at an accelerated rate compared to those grown at ambient CO2 (aCO2). Plants exposed to root-damaging insects showed a rapid decline in growth rates thereafter. In eCO2, shoot and root biomass increased by 46 and 35%, respectively, in insect-free plants but these effects were arrested when soil-dwelling insects were present so that plants were the same size as those grown at aCO2. Specific leaf mass increased by 29% under eCO2, but at eCO2 root damage caused it to decline by 16%, similar to values seen in plants at aCO2 without root damage. Leaf C:N ratio increased by >30% at eCO2 as a consequence of declining leaf N concentrations, but this change was also moderated by soil insects. Soil insects also reduced leaf water content by 9% at eCO2, which potentially arose through impaired water uptake by the roots. We hypothesise that this may have impaired photosynthetic activity to the extent that observed plant responses to eCO2 no longer occurred. In conclusion, soil-dwelling insects could modify plant responses to eCO2 predicted by climate change plant growth models.
doi:10.1371/journal.pone.0079479
PMCID: PMC3832529  PMID: 24260232
6.  Biracial and Monoracial Infant Own-Race Face Perception: An Eye Tracking Study 
Developmental science  2012;15(6):775-782.
We know early experience plays a crucial role in the development of face processing, but we know little about how infants learn to distinguish faces from different races, especially for non-Caucasian populations. Moreover, it is unknown whether differential processing of different race faces observed in typically-studied monoracial infants extends to biracial infants as well. Thus, we investigated 3-month-old Caucasian, Asian and biracial (Caucasian-Asian) infants’ ability to distinguish Caucasian and Asian faces. Infants completed two within-subject, infant-controlled habituation sequences and test trials as an eye tracker recorded looking times and scanning patterns. Examination of individual differences revealed significant positive correlations between own-race novelty preference and scanning frequency between eye and mouth regions of own-race habituation stimuli for Caucasian and Asian infants, suggesting that facility in own-race face discrimination stems from active inspection of internal facial features in these groups. Biracial infants, however, showed the opposite effect: An “own-race” novelty preference was associated with reduced scanning between eye and mouth regions of “own-race” habituation stimuli, suggesting that biracial infants use a distinct approach to processing frequently encountered faces. Future directions for investigating face processing development in biracial populations are discussed.
doi:10.1111/j.1467-7687.2012.01170.x
PMCID: PMC3490444  PMID: 23106731
infants; face perception; other race effect; intergroup processes
7.  A Hydrogel Derived From Decellularized Dermal Extracellular Matrix 
Biomaterials  2012;33(29):7028-7038.
The ECM of mammalian tissues has been used as a scaffold to facilitate the repair and reconstruction of numerous tissues. Such scaffolds are prepared in many forms including sheets, powders, and hydrogels. ECM hydrogels provide advantages such as injectability, the ability to fill an irregularly shaped space, and the inherent bioactivity of native matrix. However, material properties of ECM hydrogels and the effect of these properties upon cell behavior are neither well understood nor controlled. The objective of this study was to prepare and determine the structure, mechanics, and the cell response in vitro and in vivo of ECM hydrogels prepared from decellularized porcine dermis and urinary bladder tissues. Dermal ECM hydrogels were characterized by a more dense fiber architecture and greater mechanical integrity than urinary bladder ECM hydrogels, and showed a dose dependent increase in mechanical properties with ECM concentration. In vitro, dermal ECM hydrogels supported greater C2C12 myoblast fusion, and less fibroblast infiltration and less fibroblast mediated hydrogel contraction than urinary bladder ECM hydrogels. Both hydrogels were rapidly infiltrated by host cells, primarily macrophages, when implanted in a rat abdominal wall defect. Both ECM hydrogels degraded by 35 days in vivo, but UBM hydrogels degraded more quickly, and with greater amounts of myogenesis than dermal ECM. These results show that ECM hydrogel properties can be varied and partially controlled by the scaffold tissue source, and that these properties can markedly affect cell behavior.
doi:10.1016/j.biomaterials.2012.06.051
PMCID: PMC3408574  PMID: 22789723
8.  Young infants’ perception of the trajectories of two- and three-dimensional objects 
We investigated oculomotor anticipations in 4-month-old infants as they viewed center-occluded object trajectories. In two experiments, we examined performance in two-dimensional (2D) and three-dimensional (3D) dynamic occlusion displays and in an additional 3D condition with a smiley face as the moving target stimulus. Rates of anticipatory eye movements were not facilitated by 3D displays or by the (presumably) more salient smiley face relative to the 2D condition. However, latencies of anticipations were reduced, implying that 3D visual information may have supported formation of more robust mental representations of the moving object. Results are interpreted in a context of perceptual constraints on developing cognitive capacities during early infancy.
doi:10.1016/j.jecp.2012.04.011
PMCID: PMC3567617  PMID: 22704037
Infant perception; Depth perception; Visual development; Eye movements; Object knowledge
9.  Attentional capture by social stimuli in young infants 
We investigated the possibility that a range of social stimuli capture the attention of 6-month-old infants when in competition with other non-face objects. Infants viewed a series of six-item arrays in which one target item was a face, body part, or animal as their eye movements were recorded. Stimulus arrays were also processed for relative salience of each item in terms of color, luminance, and amount of contour. Targets were rarely the most visually salient items in the arrays, yet infants' first looks toward all three target types were above chance, and dwell times for targets exceeded other stimulus types. Girls looked longer at faces than did boys, but there were no sex differences for other stimuli. These results are interpreted in a context of learning to discriminate between different classes of animate stimuli, perhaps in line with affordances for social interaction, and origins of sex differences in social attention.
doi:10.3389/fpsyg.2013.00527
PMCID: PMC3744870  PMID: 23966966
face perception; sex differences; infant development; attention; saliency map
10.  Costs of Parkinson’s Disease in a Privately Insured Population 
Pharmacoeconomics  2013;31:799-806.
Background
This is the first analysis to estimate the costs of commercially insured patients with Parkinson’s disease (PD) in the USA. Prior analyses of PD have not examined costs in patients aged under 65 years, a majority of whom are in the workforce.
Objective
Our objective was to estimate direct and indirect costs associated with PD in patients under the age of 65 years who are newly diagnosed or have evidence of advanced PD.
Methods
PD patients were selected from a commercially insured claims database (N > 12,000,000; 1999–2009); workloss data were available for a sub-sample of enrollees. Newly diagnosed patients with evidence of similar disorders were excluded. Patients with evidence of advanced PD disease, including ambulatory assistance device users (PDAAD) and institutionalized (PDINST) patients, as well as newly diagnosed PD patients, were analyzed. Each PD cohort was age-, gender- and region-matched to controls without PD. Direct (i.e. insurer payments to providers) and indirect (i.e. workloss) costs were reported in $US, year 2010 values, and were descriptively compared using Wilcoxon rank sum tests.
Results
Patients had excess mean direct PD-related costs of $US4,072 (p < 0.001; N = 781) in the year after diagnosis. The PDAAD cohort (N = 214) had excess direct PD-related costs of $US26,467 (p < 0.001) and the PDINST cohort (N = 156) had excess direct PD-related costs of $US37,410 (p < 0.001) in the year after entering these states. Outpatient care was the most expensive cost source for newly diagnosed patients, while inpatient care was the most expensive for PDAAD and PDINST patients. Excess indirect costs were $US3,311 (p < 0.05; N = 173) in the year after initial diagnosis.
Conclusions
Direct costs for newly diagnosed PD patients exceeded costs for controls without PD, and increased with PD progression. Direct costs were approximately 6–7 times higher in patients with advanced PD than in matched controls. Indirect costs represented 45 % of total excess costs for newly diagnosed PD patients.
doi:10.1007/s40273-013-0075-0
PMCID: PMC3757266  PMID: 23907717
11.  The effect of source animal age upon the in vivo remodeling characteristics of an extracellular matrix scaffold 
Biomaterials  2012;33(22):5524-5533.
Biologic scaffolds composed of mammalian extracellular matrix (ECM) are routinely used for the repair and reconstruction of injured or missing tissues in a variety of pre-clinical and clinical applications. However, the structural and functional outcomes have varied considerably. An important variable of xenogeneic biologic scaffolds is the age of the animal from which the ECM is derived. The present study compared the in vivo host response and remodeling outcomes of biologic scaffolds composed of small intestinal submucosa (SIS)-ECM harvested from pigs that differed only in age. Results showed that there are distinct differences in the remodeling characteristics as a consequence of source animal age. Scaffolds derived from younger animals were associated with a more constructive, site appropriate, tissue remodeling response than scaffolds derived from older animals. Furthermore, the constructive remodeling response was associated with a dominant M2 macrophage response.
doi:10.1016/j.biomaterials.2012.04.017
PMCID: PMC3569720  PMID: 22575834
Age/ageing; ECM (extracellular matrix); Scaffold; Macrophage; Immune response; Mechanical properties
12.  Partial Characterization of the Sox2+ Cell Population in an Adult Murine Model of Digit Amputation 
Tissue Engineering. Part A  2012;18(13-14):1454-1463.
Tissue regeneration in response to injury in adult mammals is generally limited to select tissues. Nonmammalian species such as newts and axolotls undergo regeneration of complex tissues such as limbs and digits via recruitment and accumulation of local and circulating multipotent progenitors preprogrammed to recapitulate the missing tissue. Directed recruitment and activation of progenitor cells at a site of injury in adult mammals may alter the default wound-healing response from scar tissue toward regeneration. Bioactive molecules derived from proteolytic degradation of extracellular matrix (ECM) proteins have been shown to recruit a variety of progenitor cells in vitro and in vivo to the site of injury. The present study further characterized the population of cells accumulating at the site of injury after treatment with ECM degradation products in a well-established model of murine digit amputation. After a mid-second phalanx digit amputation in 6–8-week-old adult mice, treatment with ECM degradation products resulted in the accumulation of a heterogeneous population of cells, a subset of which expressed the transcription factor Sox2, a marker of pluripotent and adult progenitor cells. Sox2+ cells were localized lateral to the amputated P2 bone and coexpressed progenitor cell markers CD90 and Sca1. Transgenic Sox2 eGFP/+ and bone marrow chimeric mice showed that the bone marrow and blood circulation did not contribute to the Sox2+ cell population. The present study showed that, in addition to circulating progenitor cells, resident tissue-derived cells also populate at the site of injury after treatment with ECM degradation products. Although future work is necessary to determine the contribution of Sox2+ cells to functional tissue at the site of injury, recruitment and/or activation of local tissue-derived cells may be a viable approach to tissue engineering of more complex tissues in adult mammals.
doi:10.1089/ten.tea.2011.0550
PMCID: PMC3397117  PMID: 22530556
13.  Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy 
Influenza A virus infection is a major global health concern causing significant mortality, morbidity, and economic loss. Antiviral chemotherapeutics that target influenza A virus are available; however, rapid emergence of drug-resistant strains has been reported. Consequently, there is a burgeoning need to identify novel anti-influenza A drugs, particularly those that target host gene products required for virus replication, to reduce the likelihood of drug resistance. In this study, a small interfering RNA (siRNA) screen was performed to identify host druggable gene targets for anti-influenza A virus therapy. The host organic anion transporter-3 gene (OAT3), a member of the SLC22 family of transporters, was validated as being required to support influenza A virus replication. Probenecid, a prototypical uricosuric agent and chemical inhibitor of organic anion transporters known to target OAT3, was shown to be effective in limiting influenza A virus infection in vitro (50% inhibitory concentration [IC50] of 5.0 × 10−5 to 5.0 × 10−4 μM; P < 0.005) and in vivo (P < 0.05). Probenecid is widely used for treatment of gout and related hyperuricemic disorders, has been extensively studied for pharmacokinetics and safety, and represents an excellent candidate for drug repositioning as a novel anti-influenza A chemotherapeutic.
doi:10.1128/AAC.01532-12
PMCID: PMC3535968  PMID: 23129053
14.  Early Root Herbivory Impairs Arbuscular Mycorrhizal Fungal Colonization and Shifts Defence Allocation in Establishing Plantago lanceolata 
PLoS ONE  2013;8(6):e66053.
Research into plant-mediated indirect interactions between arbuscular mycorrhizal (AM) fungi and insect herbivores has focussed on those between plant shoots and above-ground herbivores, despite the fact that only below-ground herbivores share the same part of the host plant as AM fungi. Using Plantago lanceolata L., we aimed to characterise how early root herbivory by the vine weevil (Otiorhynchus sulcatus F.) affected subsequent colonization by AM fungi (Glomus spp.) and determine how the two affected plant growth and defensive chemistry. We exposed four week old P. lanceolata to root herbivory and AM fungi using a 2×2 factorial design (and quantified subsequent effects on plant biomass and iridoid glycosides (IGs) concentrations. Otiorhynchus sulcatus reduced root growth by c. 64%, whereas plant growth was unaffected by AM fungi. Root herbivory reduced extent of AM fungal colonization (by c. 61%). O. sulcatus did not influence overall IG concentrations, but caused qualitative shifts in root and shoot IGs, specifically increasing the proportion of the more toxic catalpol. These changes may reflect defensive allocation in the plant against further attack. This study demonstrates that very early root herbivory during plant development can shape future patterns of AM fungal colonization and influence defensive allocation in the plant.
doi:10.1371/journal.pone.0066053
PMCID: PMC3686864  PMID: 23840398
15.  An in vitro biomechanical comparison of Cadisc™-L with natural lumbar discs in axial compression and sagittal flexion 
European Spine Journal  2012;21(Suppl 5):612-617.
Introduction
The elastomeric, monobloc disc prosthesis (Cadisc™-L, Ranier Technology, Cambridge, UK) aims to preserve biomechanics of an implanted spinal motion segment.
Study design
This study presents the findings of an in vitro investigation on the effect of implantation of Cadisc™-L. Compressive stiffness, flexion stiffness at 10, 20, 30 and 40 Nm and the instant-axis-of-rotation (IAR) loci are compared before and after implantation of a MC-10 mm-6° Cadisc™-L.
Methods
Fresh frozen human monosegmental lumbar spines (n = 8) were prepared, potted and tested in an environmentally controlled chamber to simulate in vivo conditions. Specimens were preconditioned by loading to 500 N for 30 min. Compressive stiffness of the specimen was determined by applying pure compression of 1 kN at 250 N/s via a loading roller positioned at the central loading axis (CLA). The roller was then offset 12.5 mm anterior of the CLA and the loading regime repeated to test specimens in flexion. Bending moments were calculated from the applied load and corresponding flexion angle. The IAR locus was tracked by a motion-tracking camera.
Results
Compressive stiffness was reduced by 50 % (p = 0.0005), flexion stiffness was not statistically significantly reduced (40 % reduction, p > 0.05). IAR locus maintained a ‘horizontal figure of eight’ characteristic. Change in the locus width in the AP plane of 6.4 mm (p = 0.06) and height in the SI plane of 1.3 mm (p = 0.44) were not significant. The centroid was displaced 4.44 mm (p = 0.0019) and 5.44 mm (p = 0.025) at 3° and 6° flexion, respectively.
Conclusions
Implantation of Cadisc™-L caused a reduction in axial stiffness, but maintained disc height and flexion stiffness. IAR loci remained mobile without large displacement of the centroid from the intact spine position.
doi:10.1007/s00586-012-2249-4
PMCID: PMC3377808  PMID: 22411042
Lumbar spine; Disc replacement; Biomechanics; In vitro; Cadisc™-L
16.  The effects of auditory information on 4-month-old infants’ perception of trajectory continuity 
Child Development  2012;83(3):954-964.
Young infants perceive an object’s trajectory as continuous across occlusion provided the temporal or spatial gap in perception is small. In three experiments involving 72 participants we investigated the effects of different forms of auditory information on 4-month-olds’ perception of trajectory continuity. Provision of dynamic auditory information about the object’s trajectory enhanced perception of trajectory continuity. However, a smaller positive effect was also obtained when the sound was continuous but provided no information about the object’s location. Finally, providing discontinuous auditory information or auditory information that was dislocated relative to vision had negative effects on trajectory perception. These results are discussed relative to the intersensory redundancy hypothesis and emphasise the need to take an intersensory approach to infant perception.
doi:10.1111/j.1467-8624.2012.01739.x
PMCID: PMC3342422  PMID: 22364395
17.  Release of Plasmid DNA-Encoding IL-10 from PLGA Microparticles Facilitates Long-Term Reversal of Neuropathic Pain Following a Single Intrathecal Administration 
Pharmaceutical research  2010;27(5):841-854.
Purpose
Interleukin-10 (IL-10) is an anti-inflammatory molecule that has achieved interest as a therapeutic for neuropathic pain. In this work, the potential of plasmid DNA-encoding IL-10 (pDNA-IL-10) slowly released from biodegradable microparticles to provide long-term pain relief in an animal model of neuropathic pain was investigated.
Methods
PLGA microparticles encapsulating pDNA-IL-10 were developed and assessed both in vitro and in vivo.
Results
In vitro, pDNA containing microparticles activated macrophages, enhanced the production of nitric oxide, and increased the production of IL-10 protein relative to levels achieved with unencapsulated pDNA-IL-10. In vivo, intrathecally administered microparticles embedded in meningeal tissue, induced phagocytic cell recruitment to the cerebrospinal fluid, and relieved neuropathic pain for greater than 74 days following a single intrathecal administration, a feat not achieved with unencapsulated pDNA. Therapeutic effects of microparticle-delivered pDNA-IL-10 were blocked in the presence of IL-10-neutralizing antibody, and elevated levels of plasmid-derived IL-10 were detected in tissues for a prolonged time period post-injection (>28 days), demonstrating that therapeutic effects are dependent on IL-10 protein production.
Conclusions
These studies demonstrate that microparticle encapsulation significantly enhances the potency of intrathecally administered pDNA, which may be extended to treat other disorders that require intrathecal gene therapy.
doi:10.1007/s11095-010-0077-y
PMCID: PMC3583569  PMID: 20224990
interleukin-10; microparticle; pDNA; PLGA; neuropathic pain
18.  Statistical Learning Across Development: Flexible Yet Constrained 
Much research in the past two decades has documented infants’ and adults’ ability to extract statistical regularities from auditory input. Importantly, recent research has extended these findings to the visual domain, demonstrating learners’ sensitivity to statistical patterns within visual arrays and sequences of shapes. In this review we discuss both auditory and visual statistical learning to elucidate both the generality of and constraints on statistical learning. The review first outlines the major findings of the statistical learning literature with infants, followed by discussion of statistical learning across domains, modalities, and development. The second part of this review considers constraints on statistical learning. The discussion focuses on two categories of constraint: constraints on the types of input over which statistical learning operates and constraints based on the state of the learner. The review concludes with a discussion of possible mechanisms underlying statistical learning.
doi:10.3389/fpsyg.2012.00598
PMCID: PMC3576810  PMID: 23430452
infants; auditory statistical learning; visual statistical learning; language acquistion; learning constraints; statistical learning mechanisms
19.  Global climate change and above- belowground insect herbivore interactions 
Predicted changes to the Earth’s climate are likely to affect above–belowground interactions. Our understanding is limited, however, by past focus on two-species aboveground interactions mostly ignoring belowground influences. Despite their importance to ecosystem processes, there remains a dearth of empirical evidence showing how climate change will affect above–belowground interactions. The responses of above- and belowground organisms to climate change are likely to differ given the fundamentally different niches they inhabit. Yet there are few studies that address the biological and ecological reactions of belowground herbivores to environmental conditions in current and future climates. Even fewer studies investigate the consequences of climate change for above–belowground interactions between herbivores and other organisms; those that do provide no evidence of a directed response. This paper highlights the importance of considering the belowground fauna when making predictions on the effects of climate change on plant-mediated interspecific interactions.
doi:10.3389/fpls.2013.00412
PMCID: PMC3804764  PMID: 24155750
root; soil biota; trophic interactions; CO2; climate change; folivory
20.  Healthcare costs and utilization for privately insured patients treated for non-infectious uveitis in the USA 
Background
The purpose of this study was to describe comorbidities, healthcare costs, and resource utilization among patients with chronic non-infectious uveitis initiating corticosteroid, immunosuppressants, or biologics.
In this retrospective cohort study, patients with a non-infectious uveitis diagnosis and continuous insurance coverage during a 6-month baseline were selected from a privately insured claims database with 80.7 million enrollees. Index dates were defined as the first prescription/administration of a corticosteroid, immunosuppressant, or biologic between 2003 and 2009. Comorbidities, healthcare costs, and utilization were analyzed in a per-member-per-month (PMPM) framework to account for varying between-patient treatment periods, defined as continuous medication use within the same class. Wilcoxon rank-sum and chi-square tests were used for comparisons of costs and categorical outcomes.
Results
Patients on corticosteroids (N = 4,568), immunosuppressants (N = 5,466), and biologics (N = 1,694) formed the study population. Baseline PMPM inpatient admission rates were 0.029 for patients on corticosteroids, 0.044 for patients on immunosuppressants, and 0.045 for patients on biologics (p < 0.001 immunosuppressants or biologics versus corticosteroids); during treatment, PMPM inpatient admissions increased to 0.044 and 0.048 for patients taking corticosteroids and immunosuppressants, respectively, but decreased to 0.024 for patients taking biologics (p < 0.001 versus corticosteroids and p = 0.003 versus immunosuppressants). Baseline average PMPM costs for patients taking corticosteroids, immunosuppressants, and biologics were US$935, US$1,738, and US$1,439 (p < 0.001 between groups), while on-treatment PMPM costs excluding drug costs increased to US$1,129 for patients taking corticosteroids but lowered to US$1,592 for patients taking immunosuppressants, and US$918 for patients taking biologics (p < 0.001 versus corticosteroids or immunosuppressants).
Conclusions
There is significant economic burden associated with existing treatments of uveitis. Corticosteroids may be overused as a treatment for uveitis.
doi:10.1186/1869-5760-3-64
PMCID: PMC3830557  PMID: 24195808
Comorbidities; Healthcare costs; Healthcare utilization; Uveitis
21.  Effects of elevated temperature and CO2 on aboveground-belowground systems: a case study with plants, their mutualistic bacteria and root/shoot herbivores 
Interactions between above- and belowground herbivores have been prominent in the field of aboveground-belowground ecology from the outset, although little is known about how climate change affects these organisms when they share the same plant. Additionally, the interactive effects of multiple factors associated with climate change such as elevated temperature (eT) and elevated atmospheric carbon dioxide (eCO2) are untested. We investigated how eT and eCO2 affected larval development of the lucerne weevil (Sitona discoideus) and colonization by the pea aphid (Acyrthosiphon pisum), on three cultivars of a common host plant, lucerne (Medicago sativa). Sitona discoideus larvae feed on root nodules housing N2-fixing rhizobial bacteria, allowing us to test the effects of eT and eCO2 across trophic levels. Moreover, we assessed the influence of these factors on plant growth. eT increased plant growth rate initially (6, 8 and 10 weeks after sowing), with cultivar “Sequel” achieving the greatest height. Inoculation with aphids, however, reduced plant growth at week 14. eT severely reduced root nodulation by 43%, whereas eCO2 promoted nodulation by 56%, but only at ambient temperatures. Weevil presence increased net root biomass and nodulation, by 31 and 45%, respectively, showing an overcompensatory plant growth response. Effects of eT and eCO2 on root nodulation were mirrored by weevil larval development; eT and eCO2 reduced and increased larval development, respectively. Contrary to expectations, aphid colonization was unaffected by eT or eCO2, but there was a near-significant 10% reduction in colonization rates on plants with weevils present belowground. The contrasting effects of eT and eCO2 on weevils potentially occurred through changes in root nodulation patterns.
doi:10.3389/fpls.2013.00445
PMCID: PMC3822287  PMID: 24273544
alfalfa; aphid; lucerne; Medicago sativa; nodule; root; weevil
22.  An Isolated Cryptic Peptide Influences Osteogenesis and Bone Remodeling in an Adult Mammalian Model of Digit Amputation 
Tissue Engineering. Part A  2011;17(23-24):3033-3044.
Biologic scaffolds composed of extracellular matrix (ECM) have been used successfully in preclinical models and humans for constructive remodeling of functional, site-appropriate tissue after injury. The mechanisms underlying ECM-mediated constructive remodeling are not completely understood, but scaffold degradation and site-directed recruitment of progenitor cells are thought to play critical roles. Previous studies have identified a cryptic peptide derived from the C-terminal telopeptide of collagen IIIα that has chemotactic activity for progenitor cells. The present study characterized the osteogenic activity of the same peptide in vitro and in vivo in an adult murine model of digit amputation. The present study showed that the cryptic peptide increased calcium deposition, alkaline phosphatase activity, and osteogenic gene expression in human perivascular stem cells in vitro. Treatment with the cryptic peptide in a murine model of mid-second phalanx digit amputation led to the formation of a bone nodule at the site of amputation. In addition to potential therapeutic implications for the treatment of bone injuries and facilitation of reconstructive surgical procedures, cryptic peptides with the ability to alter stem cell recruitment and differentiation at a site of injury may serve as powerful new tools for influencing stem cell fate in the local injury microenvironment.
doi:10.1089/ten.tea.2011.0257
PMCID: PMC3226059  PMID: 21740273
23.  Recruitment of Progenitor Cells by an Extracellular Matrix Cryptic Peptide in a Mouse Model of Digit Amputation 
Tissue Engineering. Part A  2011;17(19-20):2435-2443.
Biologic scaffolds composed of extracellular matrix (ECM) have been used successfully in preclinical models and humans for constructive remodeling of functional, site-appropriate tissue after injury. The mechanisms underlying ECM-mediated constructive remodeling are not completely understood, but scaffold degradation and site-directed recruitment of both differentiated and progenitor cells are thought to play critical roles. Previous studies have shown that degradation products of ECM scaffolds can recruit a population of progenitor cells both in vitro and in vivo. The present study identified a single cryptic peptide derived from the α subunit of the collagen III molecule that is chemotactic for a well-characterized perivascular stem cell in vitro and causes the site-directed accumulation of progenitor cells in vivo. The oligopeptide was additionally chemotactic for human cortical neural stem cells, rat adipocyte stem cells, C2C12 myoblast cells, and rat Schwann cells in vitro. In an adult murine model of digit amputation, treatment with this peptide after mid-second phalanx amputation resulted in a greater number of Sox2+ and Sca1+,Lin− cells at the site of injury compared to controls. Since progenitor cell activation and recruitment are key prerequisites for epimorphic regeneration in adult mammalian tissues, endogenous site-directed recruitment of such cells has the potential to alter the default wound healing response from scar tissue toward regeneration.
doi:10.1089/ten.tea.2011.0036
PMCID: PMC3179613  PMID: 21563860
24.  The Role of Association in Early Word-Learning 
Word-learning likely involves a multiplicity of components, some domain-general, others domain-specific. Against the background of recent studies that suggest that word-learning is domain-specific, we investigated the associative component of word-learning. Seven- and 14-month-old infants viewed a pair of events in which a monkey or a truck moved back and forth, accompanied by a sung syllable or a tone, matched for pitch. Following habituation, infants were presented with displays in which the visual-auditory pairings were preserved or switched, and looked longer at the “switch” events when exposure time was sufficient to learn the intermodal association. At 7 months, performance on speech and tones conditions was statistically identical; at 14 months, infants had begun to favor speech. Thus, the associative component of word-learning does not appear (in contrast to rule-learning, Marcus et al., 2007) to initially privilege speech.
doi:10.3389/fpsyg.2012.00283
PMCID: PMC3424054  PMID: 22934086
word-learning; association; cognitive development
25.  Dissecting and Circumventing the Requirement for RAM in CSL-Dependent Notch Signaling 
PLoS ONE  2012;7(8):e39093.
The Notch signaling pathway is an intercellular communication network vital to metazoan development. Notch activation leads to the nuclear localization of the intracellular portion (NICD) of the Notch receptor. Once in the nucleus, NICD binds the transcription factor CSL through a bivalent interaction involving the high-affinity RAM region and the lower affinity ANK domain, converting CSL from a transcriptionally-repressed to an active state. This interaction is believed to directly displace co-repressor proteins from CSL and recruit co-activator proteins. Here we investigate the consequences of this bivalent organization in converting CSL from the repressed to active form. One proposed function of RAM is to promote the weak ANK:CSL interaction; thus, fusion of CSL-ANK should bypass this function of RAM. We find that a CSL-ANK fusion protein is transcriptionally active in reporter assays, but that the addition of RAM in trans further increases transcriptional activity, suggesting another role of RAM in activation. A single F235L point substitution, which disrupts co-repressor binding to CSL, renders the CSL-ANK fusion fully active and refractory to further stimulation by RAM in trans. These results suggest that in the context of a mammalian CSL-ANK fusion protein, the main role of RAM is to displace co-repressor proteins from CSL.
doi:10.1371/journal.pone.0039093
PMCID: PMC3410904  PMID: 22876274

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