The genetic basis for individual differences in mRNA splicing and APOBEC1 editing activity in murine macrophages

Alternative splicing and mRNA editing are known to contribute to transcriptome diversity. Although alternative splicing is pervasive and known to contribute to a variety of pathologies, including cancer, the genetic context for individual differences in isoform usage is still evolving. Similarly, although mRNA editing is ubiquitous and associated with important biological processes such as intracellular viral replication and cancer development, individual variations in and the genetic transmissibility of mRNA editing are equivocal. Here, we have used linkage analysis to show that both mRNA editing and alternative splicing are regulated by the macrophage genetic background and environmental cues. We show that distinct loci, potentially harboring variable splice factors, regulate the splicing of multiple transcripts. Additionally, we show that individual genetic variability at the Apobec1 locus results in differential rates of C-to-U editing in murine macrophages; with mouse strains expressing mostly a truncated isoform of Apobec1 exhibiting lower rates of editing. As a proof of concept, we have used linkage analysis to identify 36 high confidence novel edited sites. These results provide a novel and complementary method that can be used to identify C-to-U editing sites in individuals segregating at specific loci and show that, beyond individual DNA sequence and structural changes, differential isoform usage and mRNA editing can contribute to intra-species genomic and phenotypic diversity

Identification of three novel Toxoplasma gondii rhoptry proteins

The rhoptries are key secretory organelles from apicomplexan parasites that contain proteins involved in invasion and modulation of the host cell. Some rhoptry proteins are restricted to the posterior bulb (ROPs) and others to the anterior neck (RONs). As many rhoptry proteins have been shown to be key players in Toxoplasma invasion and virulence, it is important to identify, understand and characterise the biological function of the components of the rhoptries. In this report, we identified putative novel rhoptry genes by identifying Toxoplasma genes with similar cyclical expression profiles as known rhoptry protein encoding genes. Using this approach we identified two new rhoptry bulb (ROP47 and ROP48) and one new rhoptry neck protein (RON12). ROP47 is secreted and traffics to the host cell nucleus, RON12 was not detected at the moving junction during invasion. Deletion of ROP47 or ROP48 in a type II strain did not show major influence in in vitro growth or virulence in mice.United States. National Institutes of Health (R01-AI080621

Thymic Selection Determines γδ T Cell Effector Fate: Antigen-Naive Cells Make Interleukin-17 and Antigen-Experienced Cells Make Interferon γ

γδ T cells contribute uniquely to host immune competence, but how they do so remain unclear. Here, by analyzing T10/T22-specific γδ T cells in mice with different T10/T22 expression patterns, we find that encountering antigen in the thymus is neither required nor inhibitory for the development of these cells. Instead, ligand recognition determines which of two distinct functional subsets γδ T cells will become. When triggered through the TCR, lymphoid-γδ T cells that encounter ligand during development produce IFNγ, while those that develop in the absence of ligand make IL-17, a major inducer of granulopoiesis during inflammation. Indeed, we find large fractions of IL-17+ γδ T cells from the draining lymph nodes immediately after peptide/CFA immunization and days before the appearance of antigen specific IL-17+ αβ T cells. This suggests a critical role for γδ T cells as ‘initial providers’ of IL-17 in an inflammatory response to novel antigens

Calibration of myocardial T2 and T1 against iron concentration.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p<0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R2 0.566, p<0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R2 0.790, p<0.001). The relation was [Fe] = 5081•(T2)-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R2 0.517, p<0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R2 0.657, p<0.001). CONCLUSION: Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies

The Fate of Firms: Explaining Mergers and Bankruptcies

Using a uniquely complete data set of more than 50,000 observations of approximately 16,000 corporations, we test theories that seek to explain which firms become merger targets and which firms go bankrupt. We find that merger activity is much greater during prosperous periods than during recessions. In bad economic times, firms in industries with high bankruptcy rates are less likely to file for bankruptcy than they are in better years, supporting the market illiquidity arguments made by Shleifer and Vishny (1992). At the firm level, we find that, among poorly performing firms, the likelihood of merger increases with poorer performance, but among better performing firms, the relation is reversed and chances of merger increase with better performance. Such a changing relation has not been detected in prior merger studies. We also find that low-growth, resource-rich firms are prime acquisition targets and that firms’ debt capacity relates negatively to the likelihood of a merger. Debt-related variables, leverage and secured debt, play an especially prominent role in distinguishing between which firms merge and which firms go bankrupt

Measurement of the Helicity of W Bosons in Top Quark Decays

We use the transverse momentum spectrum of leptons in the decay chain t-->bW with W-->l nu to measure the helicity of the W bosons in the top quark rest frame. Our measurement uses a ttbar sample isolated in 106 +/- 4 inverse picobarns of data collected in ppbar collisions at sqrt(s)=1.8 TeV with the CDF detector at the Fermilab Tevatron. Assuming a standard V--A weak decay, we find that the fraction of W's with zero helicity in the top rest frame is F_0 = 0.91 +/- 0.37 (stat) +/- 0.13 (syst), consistent with the standard model prediction of F_0=0.70 for a top mass of 175 GeV/c**2.Comment: Submitted to PRL. 8 pages, 2 figure

Production of Y(1S) Mesons from chib Decays in pp(bar) Collisions at sqrt(s)=1.8 TeV

We have reconstructed the radiative decays $\chi_{b}(1P) \to \Upsilon(1S) \gamma$ and $\chi_{b}(2P) \to \Upsilon(1S) \gamma$ in $p \bar{p}$ collisions at $\sqrt{s} = 1.8$ TeV, and measured the fraction of $\Upsilon(1S)$ mesons that originate from these decays. For $\Upsilon(1S)$ mesons with $p^{\Upsilon}_{T}>8.0$ GeV/$c$, the fractions that come from $\chi_{b}(1P)$ and $\chi_{b}(2P)$ decays are $(27.1\pm6.9(stat)\pm4.4(sys))$ and $(10.5\pm4.4(stat)\pm1.4(sys))$, respectively. We have derived the fraction of directly produced $\Upsilon(1S)$ mesons to be $(50.9\pm8.2(stat)\pm9.0(sys))$.Comment: 13 Pages, 2 figure

Search for a Fourth-Generation Quark More Massive than the Z0 Boson in ppbar Collisions at sqrt(s) = 1.8 TeV

We present the results of a search for pair production of a fourth-generation charge -1/3 quark (b') in sqrt(s)=1.8 TeV ppbar collisions using 88 pb^(-1) of data obtained with the Collider Detector at Fermilab. We assume that both quarks decay via the flavor-changing neutral current process b' -> bZ and that the b' mass is greater than m_Z + m_b. We studied the decay mode b'b'bar -> ZZ b bbar where one Z0 decays into e^+e^- or mu^+ mu^- and the other decays hadronically, giving a signature of two leptons plus jets. An upper limit on the cross section of ppbar -> b'b'bar times [BR (b' -> bZ)]^2 is established as a function of the b' mass. We exclude at 95% confidence level a b' quark with mass between 100 and 199 GeV/c^2 for BR(b' -> bZ) = 100%.Comment: 12 pages, 2 figures, submitted to Phys. Rev. Letters on 9/12/9

Measurement of the Associated γ+μ±\gamma + \mu^\pm Production Cross Section in ppˉp \bar p Collisions at s=1.8\sqrt{s} = 1.8 TeV

We present the first measurement of associated direct photon + muon production in hadronic collisions, from a sample of 1.8 TeV $p \bar p$ collisions recorded with the Collider Detector at Fermilab. Quantum chromodynamics (QCD) predicts that these events are primarily from the Compton scattering process $cg \to c\gamma$, with the final state charm quark producing a muon. Hence this measurement is sensitive to the charm quark content of the proton. The measured cross section of $29\pm 9 pb^{-1}$ is compared to a leading-order QCD parton shower model as well as a next-to-leading-order QCD calculation.Comment: 12 pages, 4 figures Added more detailed description of muon background estimat

Measurement of the Decay Amplitudes of B0 --> J/psi K* and B0s --> J/psi phi Decays

A full angular analysis has been performed for the pseudo-scalar to vector-vector decays, B0 --> J/psi K* and B_s --> J/psi phi, to determine the amplitudes for decays with parity-even longitudinal and transverse polarization and parity-odd transverse polarization. The measurements are based on 190 B0 candidates and 40 B_s candidates collected from a data set corresponding to 89 inverse pb of pbarp collisions at root(s) = 1.8 TeV at the Fermilab Tevatron. In both decays the decay amplitude for longitudinal polarization dominates and the parity-odd amplitude is found to be small.Comment: 7 pages, 3 figures, 1 tabl