Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapyinduced leukemia

Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11–2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50–2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy

The HI Mass Function and Velocity Width Function of Void Galaxies in the Arecibo Legacy Fast ALFA Survey

We measure the HI mass function (HIMF) and velocity width function (WF) across environments over a range of masses $7.2<\log(M_{HI}/M_{\odot})<10.8$, and profile widths $1.3\log(km/s)<\log(W)<2.9\log(km/s)$, using a catalog of ~7,300 HI-selected galaxies from the ALFALFA Survey, located in the region of sky where ALFALFA and SDSS (Data Release 7) North overlap. We divide our galaxy sample into those that reside in large-scale voids (void galaxies) and those that live in denser regions (wall galaxies). We find the void HIMF to be well fit by a Schechter function with normalization $\Phi^*=(1.37\pm0.1)\times10^{-2} h^3Mpc^{-3}$, characteristic mass $\log(M^*/M_{\odot})+2\log h_{70}=9.86\pm0.02$, and low-mass-end slope $\alpha=-1.29\pm0.02$. Similarly, for wall galaxies, we find best-fitting parameters $\Phi^*=(1.82\pm0.03)\times10^{-2} h^3Mpc^{-3}$, $\log(M^*/M_{\odot})+2\log h_{70}=10.00\pm0.01$, and $\alpha=-1.35\pm0.01$. We conclude that void galaxies typically have slightly lower HI masses than their non-void counterparts, which is in agreement with the dark matter halo mass function shift in voids assuming a simple relationship between DM mass and HI mass. We also find that the low-mass slope of the void HIMF is similar to that of the wall HIMF suggesting that there is either no excess of low-mass galaxies in voids or there is an abundance of intermediate HI mass galaxies. We fit a modified Schechter function to the ALFALFA void WF and determine its best-fitting parameters to be $\Phi^*=0.21\pm0.1 h^3Mpc^{-3}$, $\log(W^*)=2.13\pm0.3$, $\alpha=0.52\pm0.5$ and high-width slope $\beta=1.3\pm0.4$. For wall galaxies, the WF parameters are: $\Phi^*=0.022\pm0.009 h^3Mpc^{-3}$, $\log(W^*)=2.62\pm0.5$, $\alpha=-0.64\pm0.2$ and $\beta=3.58\pm1.5$. Because of large uncertainties on the void and wall width functions, we cannot conclude whether the WF is dependent on the environment.Comment: Accepted for publication at MNRAS, 14 pages, 12 figure

Mutations in the E2 glycoprotein and the 3\u27 untranslated region enhance chikungunya virus virulence in mice

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes debilitating musculoskeletal pain and inflammation and can persist for months to years after acute infection. Although studies of humans and experimentally infected animals suggest that CHIKV infection persists in musculoskeletal tissues, the mechanisms for this remain poorly understood. To evaluate this further, we isolated CHIKV from the serum of persistently infected Rag1 -/- mice at day 28. When inoculated into naive wild-type (WT) mice, this persistently circulating CHIKV strain displayed a capacity for earlier dissemination and greater pathogenicity than the parental virus. Sequence analysis revealed a nonsynonymous mutation in the E2 glycoprotein (E2 K200R) and a deletion within the 3' untranslated region (3'-UTR). The introduction of these changes into the parental virus conferred enhanced virulence in mice, although primary tropism for musculoskeletal tissues was maintained. The E2 K200R mutation was largely responsible for enhanced viral dissemination and pathogenicity, although these effects were augmented by the 3'- UTR deletion. Finally, studies with Irf3/Irf7 -/- and Ifnar1 -/- mice suggest that the E2 K200R mutation enhances viral dissemination from the site of inoculation independently of interferon regulatory factor 3 (IRF3)-, IRF7-, and IFNAR1-mediated responses. As our findings reveal viral determinants of CHIKV dissemination and pathogenicity, their further study should help to elucidate host-virus interactions that determine acute and chronic CHIKV infection

Using self-definition to predict the influence of procedural justice on organizational, interpersonal, and job/task-oriented citizenship behaviors

An integrative self-definition model is proposed to improve our understanding of how procedural justice affects different outcome modalities in organizational behavior. Specifically, it is examined whether the strength of different levels of self-definition (collective, relational, and individual) each uniquely interact with procedural justice to predict organizational, interpersonal, and job/task-oriented citizenship behaviors, respectively. Results from experimental and (both single and multisource) field data consistently revealed stronger procedural justice effects (1) on organizational-oriented citizenship behavior among those who define themselves strongly in terms of organizational characteristics, (2) on interpersonal-oriented citizenship behavior among those who define themselves strongly in terms of their interpersonal relationships, and (3) on job/task-oriented citizenship behavior among those who define themselves weakly in terms of their distinctiveness or uniqueness. We discuss the relevance of these results with respect to how employees can be motivated most effectively in organizational settings

Reversing Blood Flows Act through klf2a to Ensure Normal Valvulogenesis in the Developing Heart

Heart valve anomalies are some of the most common congenital heart defects, yet neither the genetic nor the epigenetic forces guiding heart valve development are well understood. When functioning normally, mature heart valves prevent intracardiac retrograde blood flow; before valves develop, there is considerable regurgitation, resulting in reversing (or oscillatory) flows between the atrium and ventricle. As reversing flows are particularly strong stimuli to endothelial cells in culture, an attractive hypothesis is that heart valves form as a developmental response to retrograde blood flows through the maturing heart. Here, we exploit the relationship between oscillatory flow and heart rate to manipulate the amount of retrograde flow in the atrioventricular (AV) canal before and during valvulogenesis, and find that this leads to arrested valve growth. Using this manipulation, we determined that klf2a is normally expressed in the valve precursors in response to reversing flows, and is dramatically reduced by treatments that decrease such flows. Experimentally knocking down the expression of this shear-responsive gene with morpholine antisense oligonucleotides (MOs) results in dysfunctional valves. Thus, klf2a expression appears to be necessary for normal valve formation. This, together with its dependence on intracardiac hemodynamic forces, makes klf2a expression an early and reliable indicator of proper valve development. Together, these results demonstrate a critical role for reversing flows during valvulogenesis and show how relatively subtle perturbations of normal hemodynamic patterns can lead to both major alterations in gene expression and severe valve dysgenesis

Willing and able: action-state orientation and the relation between procedural justice and employee cooperation

Existing justice theory explains why fair procedures motivate employees to adopt cooperative goals, but it fails to explain how employees strive towards these goals. We study self-regulatory abilities that underlie goal striving; abilities that should thus affect employees’ display of cooperative behavior in response to procedural justice. Building on action control theory, we argue that employees who display effective self-regulatory strategies (action oriented employees) display relatively strong cooperative behavioral responses to fair procedures. A multisource field study and a laboratory experiment support this prediction. A subsequent experiment addresses the process underlying this effect by explicitly showing that action orientation facilitates attainment of the cooperative goals that people adopt in response to fair procedures, thus facilitating the display of actual cooperative behavior. This goal striving approach better integrates research on the relationship between procedural justice and employee cooperation in the self-regulation and the work motivation literature. It also offers organizations a new perspective on making procedural justice effective in stimulating employee cooperation by suggesting factors that help employees reach their adopted goals

Audience responses to representations of family-assisted suicide on British television

Reflecting on different generic conventions, this study highlights the strengths and weaknesses of documentaries and soap operas in addressing the societal and the personal dimensions of family-assisted suicide. Based on an analysis of YouTube user comments, this study compares how audience members respond to representations of family-assisted suicide in British documentaries and soap operas broadcast between 2010 and 2016. The thematic analysis of comments shows key differences between audience engagement with factual and fictional representations. Markers of a political engagement with this sensitive social issue occur more frequently in comments on documentaries than in comments on soap operas. Comments on soap operas are frequently expressions of emotion, or displays of specialist soap opera knowledge