Up Sector of Minimal Flavor Violation: Top Quark Properties and Direct D meson CP violation

Minimal Flavor Violation in the up-type quark sector leads to particularly interesting phenomenology due to the interplay of flavor physics in the charm sector and collider physics from flavor changing processes in the top sector. We study the most general operators that can affect top quark properties and $D$ meson decays in this scenario, concentrating on two CP violating operators for detailed studies. The consequences of these effective operators on charm and top flavor changing processes are generically small, but can be enhanced if there exists a light flavor mediator that is a Standard Model gauge singlet scalar and transforms under the flavor symmetry group. This flavor mediator can satisfy the current experimental bounds with a mass as low as tens of GeV and explain observed $D$-meson direct CP violation. Additionally, the model predicts a non-trivial branching fraction for a top quark decay that would mimic a dijet resonance.Comment: 27 pages, 7 figure

Sex Differences in Aripiprazole Sensitization from Adolescence to Adulthood

The present study investigated the potential sex differences in repeated aripiprazole (ARI) treatment-induced behavioral sensitization from adolescence to adulthood, and to determine whether ARI sensitization can be transferred to olanzapine (OLZ) and/or clozapine (CLZ) using the conditioned avoidance response (CAR) and phencyclidine-induced (PCP) hyperlocomotion tests of antipsychotic activity. Male and female Sprague-Dawley adolescence rats (P46) were first treated with ARI (10 mg/kg) for 5 consecutive days (P46–50) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion. After they became adults (\u3eP68), rats were challenged with ARI (1.5 mg/kg, sc) (P70), OLZ (0.5 mg/kg, sc; P73), CLZ (5 mg/kg, sc; P76) and again with ARI (1.5 mg/kg, sc; P84) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion again. During the drug treatment period in adolescence, repeated ARI treatment suppressed avoidance response, inhibited the PCP-induced hyperlocomotion, and these effects were progressively increased across the 5-day period in both males and females, confirming the induction of ARI sensitization. On the challenge days, rats previously treated with ARI in adolescence also had significantly lower avoidance and lower PCP-induced hyperlocomotion than the previous vehicle rats, confirming the expression of ARI sensitization and its persistence into adulthood. More importantly, female rats made significantly more avoidances than males in both ARI and vehicle groups, indicating higher sensitivity to the acute and long-term effects of ARI. Further, on the OLZ and CLZ challenge days, prior ARI treatment seemed to increase sensitivity to OLZ exposure, however, this increase was not significant. Similarly, rats also showed an ARI sensitization to OLZ and CLZ on challenge days. Collectively, results from this experiment demonstrated a sex difference in response to ARI and enhanced inhibition of PCP-induced hyperlocomotion in animals that were pretreated with ARI as compared to controls

Editorial: Parent, Grandparent, and Sibling Responses to the Death of an Infant or Child in Intensive Care

The death of a child is a devastating event for most parents and other family members1. However, responses to a child’s death vary by culture, generation, and often the age of the deceased child. For the Chinese, child death is a “bad death” and brings shame to the family2. Filipino parents of a deceased child feel severe guilt after their loss3. In some Caribbean cultures young mothers are prevented from attending the child’s funeral or going to the cemetery by women in the previous generation in the belief that if you “take one to the cemetery you will be taking all of your other children there as well.” In other cultures, those who die as children have not sinned, securing their place in heaven4. In the ethnically-diverse US, more than 43,000 children aged 18 and younger die each year5, most in intensive care units6. Friends, relatives, co-workers, and healthcare providers (HCP) often are uncomfortable with the parents after their child’s death, not knowing what to do, what to say, and what would help the deceased’s parents and family members. Many assume that parents and family members want to be left alone after the infant’s or child’s death. As a result, parents, siblings, and grandparents report feeling isolated and abandoned by those close to them when they need them most7–10. Little research has been done with these US family members in the difficult first year after the child’s death. What has been done has shown that studies of parents have been conducted years, even 3–7 decades11, after their infant’s or child’s death. However, many studies have very diverse samples regarding the age of the “child” at death. In some studies, family members are responding to the death of a “child” who died in childhood (≤18 years old) and a “child” who died as an adult (19 and above), sometimes as old as 40, in the same study12. In addition, studies of siblings whose brother or sister died during the sibling’s childhood are often retrospective. Some studies postpone data collection until the sibling reaches adulthood; and some studies recruit bereaved siblings when they are adults. Very few studies have been undertaken with grandparents of the deceased child. With funding from the US NIH National Institute of Nursing Research and the National Institute of General Medical Sciences, a body of research has been conducted on parents’, grandparents’ and siblings’ health and functioning during the first year after the infant’s or child’s death in the neonatal intensive care unit (NICU) or pediatric intensive care unit (PICU) to fill our knowledge gap

Nonparametric estimation of correlation functions in longitudinal and spatial data, with application to colon carcinogenesis experiments

In longitudinal and spatial studies, observations often demonstrate strong correlations that are stationary in time or distance lags, and the times or locations of these data being sampled may not be homogeneous. We propose a nonparametric estimator of the correlation function in such data, using kernel methods. We develop a pointwise asymptotic normal distribution for the proposed estimator, when the number of subjects is fixed and the number of vectors or functions within each subject goes to infinity. Based on the asymptotic theory, we propose a weighted block bootstrapping method for making inferences about the correlation function, where the weights account for the inhomogeneity of the distribution of the times or locations. The method is applied to a data set from a colon carcinogenesis study, in which colonic crypts were sampled from a piece of colon segment from each of the 12 rats in the experiment and the expression level of p27, an important cell cycle protein, was then measured for each cell within the sampled crypts. A simulation study is also provided to illustrate the numerical performance of the proposed method.Comment: Published in at http://dx.doi.org/10.1214/009053607000000082 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease

© 2008 Zhu et al. This article is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).Maintaining tolerance of T cells to self-antigens is essential to avoid autoimmune disease. How self-reactive T cells are kept functionally inactive is, however, unknown. In this study, we show that early growth response gene 2 (Egr-2), a zinc-finger transcription factor, is expressed in CD44(high) T cells and controls their proliferation and activation. In the absence of Egr-2, CD44(high), but not CD44(low) T cells, are hyperreactive and hyperproliferative in vivo. The accumulation of activated CD4(+)CD44(high) T cells leads to the development of a late onset lupuslike autoimmune disease characterized by the accumulation of interferon (IFN)-gamma and interleukin (IL)-17-producing CD4(+) T cells, loss of tolerance to nuclear antigens, massive infiltration of T cells into multiple organs and glomerulonephritis. We found that the expression of cyclin-dependent kinase inhibitor p21cip1 was impaired in Egr-2-deficient T cells, whereas the expression of IFN-gamma and IL-17 in response to T cell receptor ligation was significantly increased, suggesting that Egr-2 activates the expression of genes involved in the negative regulation of T cell proliferation and inflammation. These results demonstrate that Egr-2 is an intrinsic regulator of effector T cells and controls the expansion of self-reactive T cells and development of autoimmune disease.The Biotechnology and Biological Sciences Research Council, the Medical Research Council and the Wellcome Trust

Constructing Confidence Intervals for Effect Sizes in ANOVA Designs

A confidence interval for effect sizes provides a range of plausible population effect sizes (ES) that are consistent with data. This article defines an ES as a standardized linear contrast of means. The noncentral method, Bonett’s method, and the bias-corrected and accelerated bootstrap method are illustrated for constructing the confidence interval for such an effect size. Results obtained from the three methods are discussed and interpretations of results are offered

Handling Missing Data in Single-Case Studies

Multiple imputation is illustrated for dealing with missing data in a published SCED study. Results were compared to those obtained from available data. Merits and issues of implementation are discussed. Recommendations are offered on primal/advanced readings, statistical software, and future research

Single subject transcriptome analysis to identify functionally signed gene set or pathway activity

Analysis of single-subject transcriptome response data is an unmet need of precision medicine, made challenging by the high dimension, dynamic nature and difficulty in extracting meaningful signals from biological or stochastic noise. We have proposed a method for single subject analysis that uses a mixture model for transcript fold-change clustering from isogenically paired samples, followed by integration of these distributions with Gene Ontology Biological Processes (GO-BP) to reduce dimension and identify functional attributes. We then extended these methods to develop functional signing metrics for gene set process regulation by incorporating biological repressor relationships encoded in GO-BP as negatively regulates edges. Results revealed reproducible and biologically meaningful signals from analysis of a single subject's response, opening the door to future transcriptomic studies where subject and resource availability are currently limiting. We used inbred mouse strains fed different diets to provide isogenic biological replicates, permitting rigorous validation of our method. We compared significant genotype-specific GO-BP term results for overlap and rank order across three replicate pairs per genotype, and cross-methods to reference standards (limma+FET, SAM+FET, and GSEA). All single-subject analytics findings were robust and highly reproducible (median area under the ROC curve=0.96, n=24 genotypes x 3 replicates), providing confidence and validation of this approach for analyses in single subjects. R code is available online at http://www.lussiergroup.org/publications/PathwayActivityUniversity of Arizona Health Sciences CB2, the BIO5 Institute; NIH [U01AI122275, HL132532, CA023074, 1UG3OD023171, 1R01AG053589-01A1, 1S10RR029030]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Sphingosine 1-phosphate enhances the excitability of rat sensory neurons through activation of sphingosine 1-phosphate receptors 1 and/or 3

BACKGROUND: Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts through a family of five G-protein-coupled receptors (S1PR1-5) and plays a key role in regulating the inflammatory response. Our previous studies demonstrated that rat sensory neurons express the mRNAs for all five S1PRs and that S1P increases neuronal excitability primarily, but not exclusively, through S1PR1. This raises the question as to which other S1PRs mediate the enhanced excitability. METHODS: Isolated sensory neurons were treated with either short-interfering RNAs (siRNAs) or a variety of pharmacological agents targeted to S1PR1/R2/R3 to determine the role(s) of these receptors in regulating neuronal excitability. The excitability of isolated sensory neurons was assessed by using whole-cell patch-clamp recording to measure the capacity of these cells to fire action potentials (APs). RESULTS: After siRNA treatment, exposure to S1P failed to augment the excitability. Pooled siRNA targeted to S1PR1 and R3 also blocked the enhanced excitability produced by S1P. Consistent with the siRNA results, pretreatment with W146 and CAY10444, selective antagonists for S1PR1 and S1PR3, respectively, prevented the S1P-induced increase in neuronal excitability. Similarly, S1P failed to augment excitability after pretreatment with either VPC 23019, which is a S1PR1 and R3 antagonist, or VPC 44116, the phosphonate analog of VPC 23019. Acute exposure (10 to 15 min) to either of the well-established functional antagonists, FTY720 or CYM-5442, produced a significant increase in the excitability. Moreover, after a 1-h pretreatment with FTY720 (an agonist for S1PR1/R3/R4/R5), neither SEW2871 (S1PR1 selective agonist) nor S1P augmented the excitability. However, after pretreatment with CYM-5442 (selective for S1PR1), SEW2871 was ineffective, but S1P increased the excitability of some, but not all, sensory neurons. CONCLUSIONS: These results demonstrate that the enhanced excitability produced by S1P is mediated by activation of S1PR1 and/or S1PR3