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1.  Leptin and Leptin-Related Gene Polymorphisms, Obesity, and Influenza A/H1N1 Vaccine–Induced Immune Responses in Older Individuals 
Vaccine  2013;32(7):881-887.
Obesity is a risk factor for complicated influenza A/H1N1 disease and poor vaccine immunogenicity. Leptin, an adipocyte-derived hormone/cytokine, has many immune regulatory functions and therefore could explain susceptibility to infections and poor vaccine outcomes. We recruited 159 healthy adults (5074 years old) who were immunized with inactivated TIV influenza vacci–ne that contained A/California/7/2009/H1N1 virus. We found a strong correlation between leptin concentration and BMI (r=0.55, p<0.0001), but no association with hemagglutination antibody inhibition (HAI), B-cell, or granzyme B responses. We found a slight correlation between leptin concentration and an immunosenescence marker (TREC: T-cell receptor excision circles) level (r=0.23, p=0.01). We found eight SNPs in the LEP/LEPR/GHRL genes that were associated with leptin levels and four SNPs in the PTPN1/LEPR/STAT3 genes associated with peripheral blood TREC levels (p<0.05). Heterozygosity of the synonymous variant rs2230604 in the PTPN1 gene was associated with a significantly lower (531 vs. 259, p = 0.005) TREC level, as compared to the homozygous major variant. We also found eight SNPs in the LEP/PPARG/CRP genes associated with variations in influenza-specific HAI and B-cell responses (p<0.05). Our results suggest that specific allelic variations in the leptin-related genes may influence adaptive immune responses to influenza vaccine.
PMCID: PMC3922536  PMID: 24360890
Influenza Vaccines; Influenza A Virus; H1N1 Subtype; Immunity; Polymorphism; Single Nucleotide; Receptors; Leptin; Obesity; Adipose Tissue; Overweight; Aging; Adult; Adipocytes; A/H1N1 virus; immune response; SNPs; obese; immunosenescence; BMI
2.  Larger Extrastriate Population Receptive Fields in Autism Spectrum Disorders 
The Journal of Neuroscience  2014;34(7):2713-2724.
Previous behavioral research suggests enhanced local visual processing in individuals with autism spectrum disorders (ASDs). Here we used functional MRI and population receptive field (pRF) analysis to test whether the response selectivity of human visual cortex is atypical in individuals with high-functioning ASDs compared with neurotypical, demographically matched controls. For each voxel, we fitted a pRF model to fMRI signals measured while participants viewed flickering bar stimuli traversing the visual field. In most extrastriate regions, perifoveal pRFs were larger in the ASD group than in controls. We observed no differences in V1 or V3A. Differences in the hemodynamic response function, eye movements, or increased measurement noise could not account for these results; individuals with ASDs showed stronger, more reliable responses to visual stimulation. Interestingly, pRF sizes also correlated with individual differences in autistic traits but there were no correlations with behavioral measures of visual processing. Our findings thus suggest that visual cortex in ASDs is not characterized by sharper spatial selectivity. Instead, we speculate that visual cortical function in ASDs may be characterized by extrastriate cortical hyperexcitability or differential attentional deployment.
PMCID: PMC3921434  PMID: 24523560
autism; perceptual function; population receptive fields; retinotopy; tuning; vision
3.  Parafoveal preview during reading: Effects of sentence position 
Two experiments examined parafoveal preview for words located in the middle of sentences and at sentence boundaries. Parafoveal processing was shown to occur for words at sentence-initial, mid-sentence, and sentence-final positions. Both Experiments 1 and 2 showed reduced effects of preview on regressions out for sentence-initial words. In addition, Experiment 2 showed reduced preview effects on first-pass reading times for sentence-initial words. These effects of sentence position on preview could result from reduced parafoveal processing for sentence-initial words, or other processes specific to word reading at sentence boundaries. In addition to the effects of preview, the experiments also demonstrate variability in the effects of sentence wrap-up on different reading measures, indicating that the presence and time course of wrap-up effects may be modulated by text-specific factors. We also report simulations of Experiment 2 using version 10 of E-Z Reader (Reichle, Warren, & McConnell, 2009), designed to explore the possible mechanisms underlying parafoveal preview at sentence boundaries.
PMCID: PMC3140553  PMID: 21500948
reading; eye movements; E-Z Reader; parafoveal preview; wrap-up effects
4.  Using E-Z Reader to examine the concurrent development of eye-movement control and reading skill 
Developmental review : DR  2013;33(2):110-149.
Compared to skilled adult readers, children typically make more fixations that are longer in duration, shorter saccades, and more regressions, thus reading more slowly (Blythe & Joseph, 2011). Recent attempts to understand the reasons for these differences have discovered some similarities (e.g., children and adults target their saccades similarly; Joseph, Liversedge, Blythe, White, & Rayner, 2009) and some differences (e.g., children’s fixation durations are more affected by lexical variables; Blythe, Liversedge, Joseph, White, & Rayner, 2009) that have yet to be explained. In this article, the E-Z Reader model of eye-movement control in reading (Reichle, 2011; Reichle, Pollatsek, Fisher, & Rayner, 1998) is used to simulate various eye-movement phenomena in adults vs. children in order to evaluate hypotheses about the concurrent development of reading skill and eye-movement behavior. These simulations suggest that the primary difference between children and adults is their rate of lexical processing, and that different rates of (post-lexical) language processing may also contribute to some phenomena (e.g., children’s slower detection of semantic anomalies; Joseph et al., 2008). The theoretical implications of this hypothesis are discussed, including possible alternative accounts of these developmental changes, how reading skill and eye movements change across the entire lifespan (e.g., college-aged vs. older readers), and individual differences in reading ability.
PMCID: PMC3774954  PMID: 24058229
Computer model; Eye movements; E-Z Reader; Lexical access; Reading; Reading skill
5.  Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice 
Chemico-biological interactions  2012;203(1):212-216.
We are investigating treatments for cocaine abuse based on viral gene transfer of a cocaine hydrolase (CocH) derived from human butyrylcholinesterase, which can reduce cocaine-stimulated locomotion and cocaine-primed reinstatement of drug-seeking behavior in rats for many months. Here, in mice, we explored the possibility that anti-cocaine antibodies can complement the actions of CocH to reduce cocaine uptake in brain and block centrally-evoked locomotor stimulation. Direct injections of test proteins showed that CocH (0.3 or 1 mg/kg) was effective by itself in reducing drug levels in plasma and brain of mice given cocaine (10 mg/kg, s.c., or 20 mg/kg, i.p). Administration of cocaine antibody per se at a low dose (8 mg/kg, i.p.) exerted little effect on cocaine distribution. However, a higher dose of antibody (12 mg/kg) caused peripheral trapping (increased plasma drug levels), which led to increased cocaine metabolism by CocH, as evidenced by a 6-fold rise in plasma benzoic acid. Behavioral tests with small doses of CocH and antibody (1 and 8 mg/kg, respectively) showed that neither agent alone reduced mouse locomotor activity triggered by a very large cocaine dose (100 mg/kg, i.p.). However, dual treatment completely suppressed the locomotor stimulation. Altogether, we found cooperative and possibly synergistic actions that warrant further exploration of dual therapies for treatment of cocaine abuse.
PMCID: PMC3572300  PMID: 22960160
6.  Leptin-based Adjuvants: An Innovative Approach to Improve Vaccine Response 
Vaccine  2013;31(13):1666-1672.
Leptin is a pleiotropic hormone with multiple direct and regulatory immune functions. Leptin deficiency or resistance hinders the immunologic, metabolic, and neuroendocrinologic processes necessary to thwart infections and their associated complications, and to possibly protect against infectious diseases following vaccination. Circulating leptin levels are proportional to body fat mass. High circulating leptin concentrations, as observed in obesity, are indicative of the development of leptin transport saturation/signaling desensitization. Leptin bridges nutritional status and immunity. Although its role in vaccine response is currently unknown, over-nutrition has been shown to suppress vaccine-induced immune responses. For instance, obesity (BMI ≥ 30 kg/m2) is associated with lower antigen-specific antibody titers following influenza, hepatitis B, and tetanus vaccinations. This suggests that obesity, and possibly saturable leptin levels, are contributing factors to poor vaccine immunogenicity. While leptin-based therapies have not been investigated as vaccine adjuvants thus far, leptin’s role in immunity suggests that application of these therapies is promising and worth investigation to enhance vaccine response in people with leptin signaling impairments. This review will examine the possibility of using leptin as a vaccine adjuvant by: briefly reviewing the distribution and signal transduction of leptin and its receptors; discussing the physiology of leptin with emphasis on its immune functions; reviewing the causes of attenuation of leptin signaling; and finally, providing plausible inferences for the innovative use of leptin-based pharmacotherapies as vaccine adjuvants.
PMCID: PMC3596421  PMID: 23370154
Adipokines; Leptin; Adjuvant; Receptors, Leptin; Vaccines; Obesity; Infectious Diseases; Communicable Diseases
7.  Reading Direction and the Central Perceptual Span in Urdu and English 
PLoS ONE  2014;9(2):e88358.
Normal reading relies on the reader making a series of saccadic eye movements along lines of text, separated by brief fixational pauses during which visual information is acquired from a region of text. In English and other alphabetic languages read from left to right, the region from which useful information is acquired during each fixational pause is generally reported to extend further to the right of each fixation than to the left. However, the asymmetry of the perceptual span for alphabetic languages read in the opposite direction (i.e., from right to left) has received much less attention. Accordingly, in order to more fully investigate the asymmetry in the perceptual span for these languages, the present research assessed the influence of reading direction on the perceptual span for bilingual readers of Urdu and English.
Methods and Findings
Text in Urdu and English was presented either entirely as normal or in a gaze-contingent moving-window paradigm in which a region of text was displayed as normal at the reader's point of fixation and text outside this region was obscured. The windows of normal text extended symmetrically 0.5° of visual angle to the left and right of fixation, or asymmetrically by increasing the size of each window to 1.5° or 2.5° to either the left or right of fixation. When participants read English, performance for the window conditions was superior when windows extended to the right. However, when reading Urdu, performance was superior when windows extended to the left, and was essentially the reverse of that observed for English.
These findings provide a novel indication that the perceptual span is modified by the language being read to produce an asymmetry in the direction of reading and show for the first time that such an asymmetry occurs for reading Urdu.
PMCID: PMC3934859  PMID: 24586316
8.  Eye Movements When Reading Transposed Text: The Importance of Word-Beginning Letters 
Participants’ eye movements were recorded as they read sentences with words containing transposed adjacent letters. Transpositions were either external (e.g., problme, rpoblem) or internal (e.g., porblem, probelm) and at either the beginning (e.g., rpoblem, porblem) or end (e.g., problme, probelm) of words. The results showed disruption for words with transposed letters compared to the normal baseline condition, and the greatest disruption was observed for word-initial transpositions. In Experiment 1, transpositions within low frequency words led to longer reading times than when letters were transposed within high frequency words. Experiment 2 demonstrated that the position of word-initial letters is most critical even when parafoveal preview of words to the right of fixation is unavailable. The findings have important implications for the roles of different letter positions in word recognition and the effects of parafoveal preview on word recognition processes.
PMCID: PMC2662926  PMID: 18823209
reading; eye movements; word recognition; transposed letters; parafoveal processing
9.  Measles, Mumps, and Rubella 
Measles, mumps, and rubella are viral diseases that may adversely affect non-immune pregnant women and their fetuses/neonates. Prevention of these diseases and their complications can be achieved through measles-mumps-rubella (MMR) vaccination prior to pregnancy. The vaccine is contraindicated during pregnancy because it contains live, attenuated viruses that pose a theoretical risk to the fetus. However, accidental receipt of MMR vaccination is not known to cause maternal/fetal complications. MMR immunization is recommended to non-immune obstetric patients upon completion or termination of pregnancy.
PMCID: PMC3334858  PMID: 22510638
Measles-Mumps-Rubella Vaccine; Measles; Mumps; Rubella; Congenital Rubella Syndrome; Obstetrics
10.  Replication of Associations between Cytokine and Cytokine Receptor Single Nucleotide Polymorphisms and Measles-Specific Adaptive Immunophenotypic Extremes 
Human Immunology  2012;73(6):636-640.
Our objective was to replicate previously reported associations between cytokine and cytokine receptor SNPs and humoral and CMI (cell-mediated immune) responses to measles vaccine. All subjects (n=758) received two doses of MMR (measles/mumps/rubella) vaccine. From these subjects, candidate cytokine and cytokine receptor SNPs were genotyped and analyzed in 29–30 subjects falling into one of four “extreme” humoral (Abhigh/low) and CMI (CMIhigh/low) response quadrants. Associations between seven SNPs (out of 11 in the discovery study) and measles-specific neutralizing antibody levels and IFN-γ ELISPOT responses were evaluated using chi-square tests. We found one replicated association for SNP rs372889 in the IL12RB1 gene (P=0.03 for AbhighCMIhigh versus AblowCMIlow). Our findings demonstrate the importance of replicating genotypic-phenotypic associations, which can be achieved using immunophenotypic extremes and smaller sample sizes. We speculate that IL12RB1 polymorphisms may affect IL-12 and IL-23 binding and downstream effects, which are critical cytokines in the CMI response to measles vaccine.
PMCID: PMC3368081  PMID: 22504412
Measles immunity; SNP; Cytokine Receptor; IL12RB1; Replication Study
11.  Exploring the building blocks of social cognition: spontaneous agency perception and visual perspective taking in autism 
Individuals with autism spectrum disorders have highly characteristic impairments in social interaction and this is true also for those with high functioning autism or Asperger syndrome (AS). These social cognitive impairments are far from global and it seems likely that some of the building blocks of social cognition are intact. In our first experiment, we investigated whether high functioning adults who also had a diagnosis of AS would be similar to control participants in terms of their eye movements when watching animated triangles in short movies that normally evoke mentalizing. They were. Our second experiment using the same movies, tested whether both groups would spontaneously adopt the visuo-spatial perspective of a triangle protagonist. They did. At the same time autistic participants differed in their verbal accounts of the story line underlying the movies, confirming their specific difficulties in on-line mentalizing. In spite of this difficulty, two basic building blocks of social cognition appear to be intact: spontaneous agency perception and spontaneous visual perspective taking.
PMCID: PMC3190214  PMID: 20934986
theory of mind; mental state; social cognition; eye movements; triangle animations
12.  Distributional Effects of Word Frequency on Eye Fixation Durations 
Recent research using word recognition paradigms such as lexical decision and speeded pronunciation has investigated how a range of variables affect the location and shape of response time distributions, using both parametric and non-parametric techniques. In this article, we explore the distributional effects of a word frequency manipulation on fixation durations in normal reading, making use of data from two recent eye movement experiments (Drieghe, Rayner, & Pollatsek, 2008; White, 2008). The ex-Gaussian distribution provided a good fit to the shape of individual subjects’ distributions in both experiments. The frequency manipulation affected both the shift and skew of the distributions, in both experiments, and this conclusion was supported by the non-parametric vincentizing technique. Finally, a new experiment demonstrated that White’s (2008) frequency manipulation also affects both shift and skew in RT distributions in the lexical decision task. These results argue against models of eye movement control in reading that propose that word frequency influences only a subset of fixations, and support models in which there is a tight connection between eye movement control and the progress of lexical processing.
PMCID: PMC2948239  PMID: 20873939
13.  Vulnerability to (+)-Methamphetamine Effects and the Relationship to Drug Disposition in Pregnant Rats during Chronic Infusion 
Toxicological Sciences  2009;111(1):27-36.
Chronic (+)-methamphetamine (METH) use during pregnancy increases the health risk for both mother and fetus. To provide insights into these risks, the relationship between changes in METH disposition and METH-induced pharmacological effects were studied in Sprague-Dawley rat dams and litters. Timed-pregnant rats (n = 5–6) were given saline or METH (5.6–17.8 mg/kg/day) by continuous sc infusion from gestational day (GD) 7 (before organogenesis) until GD21 (0–2 days before delivery). By GD11, all rats in the 17.8-mg/kg/day group died or were sacrificed for humane reasons. There were significant (p < 0.05) dose- and gestational time-dependent decreases in maternal body weight in the 10- to 13.2-mg/kg/day groups, which slowly recovered to near normal by GD21. Continued METH dosing in the surviving groups did not affect the mean pups/litter weight at the end of the experiment on GD21. While maternal and fetal METH and (+)-amphetamine serum concentrations were similar on GD21, brain concentrations were significantly greater in the dams (p < 0.05). Importantly, brain-to-serum ratios in the dams were 9:1 and 3:1 in the pups. METH systemic clearance (ClS) in dams significantly (p < 0.05) decreased from 52 ± 14 ml/min/kg on GD10 to 28 ± 6 ml/min/kg on GD21 in all dose groups, indicating late-gestational stage reductions in METH ClS. Overall, these findings suggest that there were two periods of increased susceptibility for dams and fetuses during chronic METH treatment. First was the period after the start of METH dosing in which neuroadaptation and tolerance to METH occurs in the adult. The second was at the end of pregnancy when METH clearance was significantly reduced.
PMCID: PMC2726297  PMID: 19520673
methamphetamine; pregnancy; rat; drug abuse; pharmacokinetics
14.  Visual information capture during fixations in reading for children and adults 
Vision research  2009;49(12):1583-1591.
Two experiments were undertaken to examine whether there is an age-related change in the speed with which readers can capture visual information during fixations in reading. Children’s and adults’ eye movements were recorded as they read sentences that were presented either normally or as “disappearing text”. The disappearing text manipulation had a surprisingly small effect on the children, inconsistent with the notion of an age-related change in the speed with which readers can capture visual information from the page. Instead, we suggest that differences between adults and children are related to the level of difficulty of the sentences for readers of different ages.
PMCID: PMC2692560  PMID: 19328823
children; eye movements; reading
15.  Investigating the causes of wrap-up effects: Evidence from eye movements and E-Z Reader 
Cognition  2009;111(1):132-137.
Wrap-up effects in reading have traditionally been thought to reflect increased processing associated with intra- and inter-clause integration (Just & Carpenter, 1980; Rayner, Kambe & Duffy, 2000; cf. Hirotani, Frazier, & Rayner, 2006). We report an eye-tracking experiment with a strong manipulation of integrative complexity at a critical word that was either sentence-final, ended a comma-marked clause, or was not comma marked. Although both complexity and punctuation each had reliable effects, they did not interact in any eye-movement measure. These results and simulations using the E-Z Reader model of eye-movement control (Reichle, Warren, & McConnell, 2009) suggest that traditional accounts of clause wrap-up are incomplete.
PMCID: PMC2682724  PMID: 19215911
16.  Eye Movements and the Use of Parafoveal Word Length Information in Reading 
Eye movements were monitored in 4 experiments that explored the role of parafoveal word length in reading. The experiments employed a type of compound word where the deletion of a letter results in 2 short words (e.g., backhand, back and). The boundary technique (K. Rayner, 1975) was employed to manipulate word length information in the parafovea. Accuracy of the parafoveal word length preview significantly affected landing positions and fixation durations. This disruption was larger for 2-word targets, but the results demonstrated that this interaction was not due to the morphological status of the target words. Manipulation of sentence context also demonstrated that parafoveal word length information can be used in combination with sentence context to narrow down lexical candidates. The 4 experiments converge in demonstrating that an important role of parafoveal word length information is to direct the eyes to the center of the parafoveal word.
PMCID: PMC2668122  PMID: 19045993
eye movements; reading; parafoveal length information
17.  Children’s and adults’ processing of anomaly and implausibility during reading: Evidence from eye movements 
The eye movements of 24 children and 24 adults were monitored to compare how they read sentences containing plausible, implausible, and anomalous thematic relations. In the implausible condition the incongruity occurred due to the incompatibility of two objects involved in the event denoted by the main verb. In the anomalous condition the direct object of the verb was not a possible verb argument. Adults exhibited immediate disruption with the anomalous sentences as compared to the implausible sentences as indexed by longer gaze durations on the target word. Children exhibited the same pattern of effects as adults as far as the anomalous sentences were concerned, but exhibited delayed effects of implausibility. These data indicate that while children and adults are alike in their basic thematic assignment processes during reading, children may be delayed in the efficiency with which they are able to integrate pragmatic and real-world knowledge into their discourse representation.
PMCID: PMC2662929  PMID: 17853235

Results 1-17 (17)