Control and maintenance of mammalian cell size: Response

A response to Cooper S: Control and maintenance of mammalian cell size. BMC Cell Biol 2004, 5:3

Concrete Language and Sexual Prejudice

This paper examines the role of concrete terminology in survey research and its relationship to prejudicial response. Using data from the 2004 National Annenberg Election Study, I examine responses to two similarly worded items about same-sex marriage. The two questions had near-identical wording, with the only exception being the terms used to refer to describe same-sex couples. The first wording asked about "gays and lesbians," whereas the second asked about "two men" or "two women." Drawing on research in cognitive psychology, I hypothesize that opposition to the second wording will be higher and more extreme because the wording is more concrete and thus more likely to evoke visualization. Additionally, I hypothesize that respondents from sociodemographic groups associated with heightened sexual prejudice will be disproportionately affected by the concrete wording. The results confirm both hypotheses. Implications for survey response and limitations of the current study are discussed

Modification of Decay Constants of Superstring Axions: Effects of Flux Compactification and Axion Mixing

We study possibilities for lowering the decay constants of superstring axions. In the heterotic Calabi-Yau compactification, a localized model-dependent axion can appear at a nearly collapsing 2-cycle. The effect of flux can be used for generating warp factor suppression of the axion decay constant. We also point out that the hidden sector instanton potential much higher than the QCD instanton potential picks up the larger effective axion decay constant as that of the QCD axion. We show that this can be converted by introducing many hidden-sector quarks so that the decay constant of the QCD axion turns out to be much smaller than the string scale.Comment: 6 pages with 3 figures, revtex; figure added,section of axion mixing modifie

String compactification, QCD axion and axion-photon-photon coupling

It is pointed out that there exist a few problems to be overcome toward an observable sub-eV QCD axion in superstring compactification. We give a general expression for the axion decay constant. For a large domain wall number $N_{DW}$, the axion decay constant can be substantially lowered from a generic value of a scalar singlet VEV. The Yukawa coupling structure in the recent $Z_{12-I}$ model is studied completely, including the needed nonrenormalizable terms toward realistic quark and lepton masses. In this model we find an approximate global symmetry and vacuum so that a QCD axion results but its decay constant is at the GUT scale. The axion-photon-photon coupling is calculated for a realistic vacuum satisfying the quark and lepton mass matrix conditions. It is the first time calculation of $c_{a\gamma\gamma}$ in realistic string compactifications: $c_{a\gamma\gamma}={5/3}-1.93\simeq -0.26$.Comment: 33 pages, 2 figures, JHEP format, some errors in the superpotential couplings are corrected and the following discussions are changed correspondingl

Neglected Ethical Issues in Biobank Management: Results from a U.S. Study

Abstract The empirical literature on the ethical, legal, and social implications (ELSI) of biobanking has almost entirely relied on the perspectives of those outside of biobanks, such as the general public, researchers, and specimen contributors. Little attention has been paid to the perspectives and practices of those who operate biobanks. We conducted a study of U.S. biobanks consisting of six in-depth case studies and a large online survey (N = 456), which was developed from the case study results. The case studies included qualitative interviews with a total of 24 personnel. Both interview and survey questions focused on how biobanks operate, and what policies and practices govern their relationships with specimen contributors and the researchers who use the specimens. Analysis revealed unexpected ethical dilemmas embedded in those policies and practices that highlight a need for practical planning. In this paper, we review three issues seldom explored in the ELSI literature: 1. the discrepancy between biobankers’ hope that the bank will exist “permanently” and the fact that funding is limited; 2. the lack of planning for what will happen to the specimens if the bank closes; and 3. the concern that once collected, specimens may be underutilized. These dilemmas are missing from current public representations of biobanks, which instead focus on the intrinsic value in storing specimens as essential to the advancement of translational research. We argue that attention to these issues is important for biobanking, and that greater transparency of these policies and practices will contribute to promoting public trust in biobanks

Stewardship Practices of U.S. Biobanks

Biobanks require new governance models that address their ethical and regulatory challenges. One model relies on stewardship of specimens throughout their life course. Here, we discuss findings from our survey of 456 U.S. biobank managers that addressed whether and how biobanks steward their specimens. The findings reveal that most bio-banks do not create ongoing relationships with contributors but do practice stewardship over storing and sharing of specimens. Biobanks now need guidance to fully articulate stewardship practices that ensure respect for contributors while facilitating research

The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation

Human mutations in the cardiac transcription factor gene TBX5 cause Congenital Heart Disease (CHD), however the underlying mechanism is unknown. We report characterization of the endogenous TBX5 cardiac interactome and demonstrate that TBX5, long considered a transcriptional activator, interacts biochemically and genetically with the Nucleosome Remodeling and Deacetylase (NuRD) repressor complex. Incompatible gene programs are repressed by TBX5 in the developing heart. CHD missense mutations that disrupt the TBX5-NuRD interaction cause depression of a subset of repressed genes. Furthermore, the TBX5-NuRD interaction is required for heart development. Phylogenetic analysis showed that the TBX5-NuRD interaction domain evolved during early diversification of vertebrates, simultaneous with the evolution of cardiac septation. Collectively, this work defines a TBX5-NuRD interaction essential to cardiac development and the evolution of the mammalian heart, and when altered may contribute to human CHD

Investigation of relationships between bipolar disorder phenotypes and genome-wide significant loci from PGC2 schizophrenia

Background Schizophrenia (SZ) and Bipolar disorder (BD) show evidence for partial overlap in phenotypic and genetic influences based on family, twins, adoption and Psychiatric Genetic Consortium (PGC) studies. They have lifetime prevalence of about 1% and 2.4%, and heritability estimates of 60-80% and 40-70%, respectively. In the last decade BD has been investigated using dimensional structuring of psychoses based on symptomatic-functional checklists that provides reliable approach to phenotypic assessment. Recent research suggests moving towards developing Phenotype-based Genetic Association Studies. In this approach, patients will only be put into groups consisting of others with symptoms similar to their own. Canonical Correlation Analysis (CCA) is statistical technique designed to identify relationships (usually hidden) between two sets of variables. We use CCA to combine genotypic and phenotypic variables and measure correlation between those sets. This analysis estimates canonical correlation between psychotic symptoms measured using validated item check list (OPCRIT), and genome-wide significant (GWS) loci from PGC2 schizophrenia. Methods For our analysis we used phenotype and genetic data for 5,507 BD cases. Imputation of genetic data was performed with 1000Genomes (Phase 3, 2014) then quality control was applied (INFO>0.8, HWE>1e-6, MAF>0.01). Additional quality control was performed on phenotypic symptom coverage. CCA was employed as implemented in R, using package “CCA” with GWS loci from PGC2 SZ and OPCRIT items. SNPs were standardised and adjusted for 10 population covariates calculated from imputed data using principal component approach prior to CCA. Results Canonical correlation analysis was run on 4422 cases on 89 available GWS PGC2 SZ SNPs or their proxies (with r2>0.6). 60 phenotypic variables were taken from OPCRIT measurements including mood disturbance, biological indices, atypical depression, substance use, psychosis and social functioning. We found no significant canonical correlations indicating absence of hidden sub-clusters at individual symptom level of BD associated with SZ GWS loci. Discussion Our analysis was focused to find correlation from bipolar phenotype by using OPCRIT questionnaire and GWS SZ loci from PGC2. We have shown that there were no significant canonical correlation coefficients suggesting that there is no direct association between SZ associated genetic loci and BP at individual symptom level. CCA is canonical correlation analysis is one of potential of data-driven approaches to identify hidden genotype-phenotype relationships. It provides opportunities to generate and test different hypotheses and understand more about complex architecture of psychiatric disorders. In the next stage we plan to extend our analysis to more fine grained systematic descriptors of BD and test for correlation with genetic profiles from a number of co-morbid disorders, as well as the full range of phenotypic and genetic data that are available

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10(−5) to 10(−3). Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD