Absence of Donor-Specific Anti-HLA Antibodies After ABO-Incompatible Heart Transplantation in Infancy: Altered Immunity or Age?

Specific B-cell tolerance toward donor blood group antigens develops in infants after ABO-incompatible heart transplantation, whereas their immune response toward protein antigens such as HLA has not been investigated. We assessed de novo HLA-antibodies in 122 patients after pediatric thoracic transplantation (28 ABO-incompatible) and 36 controls. Median age at transplantation was 1.7 years (1 day to 17.8 year) and samples were collected at median 3.48 years after transplantation. Antibodies were detected against HLA-class I in 21 patients (17.2%), class II in 18 (14.8%) and against both classes in 10 (8.2%). Using single-antigen beads, donor-specific antibodies (DSAs) were identified in six patients (all class II, one additional class I). Patients with DSAs were significantly older at time of transplantation. In patients who had undergone pretransplant cardiac surgeries, class II antibodies were more frequent, although use of homografts or mechanical heart support had no influence. DSAs were absent in ABO-incompatible recipients and class II antibodies were significantly less frequent than in children with ABO-compatible transplants. This difference was present also when comparing only children transplanted below 2 years of age. Therefore, tolerance toward the donor blood group appears to be associated with an altered response to HLA beyond age-related effects.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78721/1/j.1600-6143.2009.02877.x.pd

Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate

Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10-6<P<10-4) in a test for GxETS interaction. SNPs rs3733585 and rs12508991 in SLC2A9 yielded P = 2.26×10-7 in a test for GxETS interaction. SNPs rs6820756 and rs7699512 in WDR1 also yielded P = 1.79×10-7 and P = 1.98×10-7 in a 1 df test for GxE interaction. Although further replication studies are critical to confirming these findings, these results illustrate how genetic associations for nonsyndromic CP can be missed if potential GxE interaction is not taken into account, and this study suggest SLC2A9 and WDR1 should be considered as candidate genes for CP. © 2014 Wu et al

Transcriptional Enhancers in Protein-Coding Exons of Vertebrate Developmental Genes

Many conserved noncoding sequences function as transcriptional enhancers that regulate gene expression. Here, we report that protein-coding DNA also frequently contains enhancers functioning at the transcriptional level. We tested the enhancer activity of 31 protein-coding exons, which we chose based on strong sequence conservation between zebrafish and human, and occurrence in developmental genes, using a Tol2 transposable GFP reporter assay in zebrafish. For each exon we measured GFP expression in hundreds of embryos in 10 anatomies via a novel system that implements the voice-recognition capabilities of a cellular phone. We find that 24/31 (77%) exons drive GFP expression compared to a minimal promoter control, and 14/24 are anatomy-specific (expression in four anatomies or less). GFP expression driven by these coding enhancers frequently overlaps the anatomies where the host gene is expressed (60%), suggesting self-regulation. Highly conserved coding sequences and highly conserved noncoding sequences do not significantly differ in enhancer activity (coding: 24/31 vs. noncoding: 105/147) or tissue-specificity (coding: 14/24 vs. noncoding: 50/105). Furthermore, coding and noncoding enhancers display similar levels of the enhancer-related histone modification H3K4me1 (coding: 9/24 vs noncoding: 34/81). Meanwhile, coding enhancers are over three times as likely to contain an H3K4me1 mark as other exons of the host gene. Our work suggests that developmental transcriptional enhancers do not discriminate between coding and noncoding DNA and reveals widespread dual functions in protein-coding DNA

Gain-Loss Separability and Coalescing in Risky Decision Making Short Title: Gain-Loss Separability and Coalescing Filename: Gain_loss_paper_05_31_06.doc Contact Info: Mailing address:

This experiment tested two behavioral properties of risky decision making, gain-loss separability and coalescing. Cumulative prospect theory (CPT) implies both properties, but the transfer of attention exchange model (TAX) violates both. Original prospect theory satisfies gain-loss separability but may or may not satisfy coalescing, depending on whether editing rules are assumed. A configural form of CPT proposed by Wu and Markle violates gain-loss separability but satisfies coalescing. New tests were designed and conducted to test these theories against specific predictions of a TAX model. This model used parameters estimated from previous data together with simple new assumptions to extend TAX to gambles with negative and mixed consequences. Contrary to all three forms of prospect theory, systematic violations of both coalescing and of gain-loss separability were observed. Violations of GLS were confirmed by analyses of individual data patterns by means of an error model in which each choice can have a different rate of error. Without estimating any parameters from the new data, the TAX model predicted the majority choices in the new data fairly well, correctly predicting when modal choices would violate gain-loss separability, when they would satisfy it, and when indifference would be observed.

Separating response variability from structural inconsistency to test models of risky decision making

Individual true and error theory assumes that responses by the same person to the same choice problem within a block of trials are based on the same true preferences but may show preference reversals due to random error. Between blocks, a person{}'s true preferences may differ or stay the same. This theory is illustrated with studies testing two critical properties that distinguish models of risky decision making: (1) restricted branch independence, which is implied by original prospect theory and violated in a specific way by both cumulative prospect theory and the priority heuristic; and (2) stochastic dominance, which is implied by cumulative prospect theory. Corrected for random error, most individuals systematically violated stochastic dominance, ruling out cumulative prospect theory. Furthermore, most people violated restricted branch independence in the opposite way predicted by that theory and the priority heuristic. Both violations are consistent with the transfer of attention exchange model. No one was found whose data were compatible with cumulative prospect theory, except for those that were also compatible with expected utility, and no one satisfied the priority heuristic

Testing transitivity of preferences using linked designs

Three experiments tested if individuals show violations of transitivity in choices between risky gambles in linked designs. The binary gambles varied in the probability to win the higher (better) prize, the value of the higher prize, and the value of the lower prize. Each design varied two factors, with the third fixed. Designs are linked by using the same values in different designs. Linked designs allow one to determine if a lexicographic semiorder model can describe violations of transitivity in more than one design using the same parameters. In addition, two experiments tested interactive independence, a critical property implied by all lexicographic semiorder models. Very few people showed systematic violations of transitivity; only one person out of 136 showed violations of transitivity in two designs that could be linked by a lexicographic semiorder. However, that person violated interactive independence, as did the majority of other participants. Most individuals showed systematic violations of the assumptions of stochastic independence and stationarity of choice responses. That means that investigators should evaluate models with respect to response patterns (response combinations) rather than focusing entirely on choice proportions

Gain-Loss Separability and Coalescing in Risky Decision Making

This experiment tested two behavioral properties of risky decision making—gain-loss separability (GLS) and coalescing. Cumulative prospect theory (CPT) implies both properties, but the transfer of attention exchange (TAX) model violates both. Original prospect theory satisfies GLS but may or may not satisfy coalescing, depending on whether editing rules are assumed. A configural form of CPT proposed by Wu and Markle [Wu, G., A. B. Markle. 2004. An empirical test of gain-loss separability in prospect theory. Working Paper 06-25-04, Graduate School of Business, University of Chicago] violates GLS, but satisfies coalescing. New tests were designed and conducted to test these theories against specific predictions of a TAX model. This model used parameters estimated from previous data, together with simple new assumptions to extend TAX to gambles with negative and mixed consequences. Contrary to all three forms of prospect theory, systematic violations of both coalescing and GLS were observed. Violations of GLS were confirmed by analyses of individual data patterns by means of an error model in which each choice can have a different rate of error. Without estimating any parameters from the new data, the TAX model predicted the majority choices in the new data fairly well, correctly predicting when modal choices would violate GLS, when they would satisfy it, and when indifference would be observed