Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation. Methods: Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease. Results: The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN. Conclusions: A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM

Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis

Methadone is a widely used therapeutic opioid in narcotic addiction and neuropathic pain syndromes. Oncologists regularly use methadone as a long-lasting analgesic. Recently it has also been proposed as a promising agent in leukemia therapy, especially when conventional therapies are not effective. Nevertheless, numerous reports indicate a negative impact on human cognition with chronic exposure to opiates. Thus, clarification of methadone toxicity is required. In SH-SY5Y cells we found that high concentrations of methadone were required to induce cell death. Methadone-induced cell death seems to be related to necrotic processes rather than typical apoptosis. Cell cultures challenged with methadone presented alterations in mitochondrial outer membrane permeability. A mechanism that involves Bax translocation to the mitochondria was observed, accompanied with cytochrome c release. Furthermore, no participation of known protein regulators of apoptosis such as Bcl-XL and p53 was observed. Interestingly, methadone induced cell death took place by a caspases-independent pathway; perhaps due to its ability to induce a drastic depletion in cellular ATP levels. Therefore, we studied the effect of methadone on isolated rat liver mitochondria. We observed that methadone caused mitochondrial uncoupling, coinciding with the ionophoric properties of methadone, but did not cause swelling of the organelles. Overall, the effects observed for cells in the presence of supratherapeutic doses of methadone may result from a “bioenergetic crisis.” A decreased level of cellular energy may predispose cells to necrotic-like cell death

Evidence for t\bar{t}\gamma Production and Measurement of \sigma_t\bar{t}\gamma / \sigma_t\bar{t}

Using data corresponding to 6.0/fb of ppbar collisions at sqrt(s) = 1.96 TeV collected by the CDF II detector, we present a cross section measurement of top-quark pair production with an additional radiated photon. The events are selected by looking for a lepton, a photon, significant transverse momentum imbalance, large total transverse energy, and three or more jets, with at least one identified as containing a b quark. The ttbar+photon sample requires the photon to have 10 GeV or more of transverse energy, and to be in the central region. Using an event selection optimized for the ttbar+photon candidate sample we measure the production cross section of, and the ratio of cross sections of the two samples. Control samples in the dilepton+photon and lepton+photon+\met, channels are constructed to aid in decay product identification and background measurements. We observe 30 ttbar+photon candidate events compared to the standard model expectation of 26.9 +/- 3.4 events. We measure the ttbar+photon cross section to be 0.18+0.08 pb, and the ratio of the cross section of ttbar+photon to ttbar to be 0.024 +/- 0.009. Assuming no ttbar+photon production, we observe a probability of 0.0015 of the background events alone producing 30 events or more, corresponding to 3.0 standard deviations.Comment: 9 pages, 3 figure

Precision Top-Quark Mass Measurements at CDF

We present a precision measurement of the top-quark mass using the full sample of Tevatron $\sqrt{s}=1.96$ TeV proton-antiproton collisions collected by the CDF II detector, corresponding to an integrated luminosity of 8.7 $fb^{-1}$. Using a sample of $t\bar{t}$ candidate events decaying into the lepton+jets channel, we obtain distributions of the top-quark masses and the invariant mass of two jets from the $W$ boson decays from data. We then compare these distributions to templates derived from signal and background samples to extract the top-quark mass and the energy scale of the calorimeter jets with {\it in situ} calibration. The likelihood fit of the templates from signal and background events to the data yields the single most-precise measurement of the top-quark mass, \mtop = 172.85 \pm$0.71 (stat)$\pm$0.85 (syst) GeV/c^{2}.$Comment: submitted to Phys. Rev. Let

Measurement of branching ratio and Bs0 lifetime in the decay Bs0 -> J/psi f0(980) at CDF

We present a study of Bs0 decays to the CP-odd final state J/psi f0(980) with J/psi -> mu+ mu- and f0(980) -> pi+ pi-. Using ppbar collision data with an integrated luminosity of 3.8/fb collected by the CDF II detector at the Tevatron we measure a Bs0 lifetime of tau(Bs0 -> J/psi f0(980)) = 1.70 -0.11+0.12(stat) +-0.03(syst) ps. This is the first measurement of the Bs0 lifetime in a decay to a CP eigenstate and corresponds in the standard model to the lifetime of the heavy Bs0 eigenstate. We also measure the product of branching fractions of Bs0 -> J/psi f0(980) and f0(980) -> pi+ pi- relative to the product of branching fractions of Bs0 -> J/psi phi and phi -> K+ K- to be R_f0/phi = 0.257 +_0.020(stat) +-0.014(syst), which is the most precise determination of this quantity to date.Comment: accepted by Phys. Rev.

Measurement of the ttbar Production Cross Section in ppbar Collisions at sqrt(s) = 1.96 TeV

We present a measurement of the top quark pair production cross section in ppbar collisions at sqrt(s)=1.96 TeV using 318 pb^{-1} of data collected with the Collider Detector at Fermilab. We select ttbar decays into the final states e nu + jets and mu nu + jets, in which at least one b quark from the t-quark decays is identified using a secondary vertex-finding algorithm. Assuming a top quark mass of 178 GeV/c^2, we measure a cross section of 8.7 +-0.9 (stat) +1.1-0.9 (syst) pb. We also report the first observation of ttbar with significance greater than 5 sigma in the subsample in which both b quarks are identified, corresponding to a cross section of 10.1 +1.6-1.4(stat)+2.0-1.3 (syst) pb.Comment: Accepted for publication in Physics Review Letters, 7 page

Measurement of the Helicity Fractions of W Bosons from Top Quark Decays Using Fully Reconstructed top-antitop Events with CDF II

We present a measurement of the fractions F_0 and F_+ of longitudinally polarized and right-handed W bosons in top quark decays using data collected with the CDF II detector. The data set used in the analysis corresponds to an integrated luminosity of approximately 318 pb -1. We select ttbar candidate events with one lepton, at least four jets, and missing transverse energy. Our helicity measurement uses the decay angle theta*, which is defined as the angle between the momentum of the charged lepton in the W boson rest frame and the W momentum in the top quark rest frame. The cos(theta*) distribution in the data is determined by full kinematic reconstruction of the ttbar candidates. We find F_0 = 0.85 +0.15 -0.22 (stat) +- 0.06 (syst) and F_+ = 0.05 +0.11 -0.05 (stat) +- 0.03 (syst), which is consistent with the standard model prediction. We set an upper limit on the fraction of right-handed W bosons of F_+ < 0.26 at the 95% confidence level.Comment: 11 pages, 2 figures, submitted to Phys. Rev.

Search for the Higgs boson in events with missing transverse energy and b quark jets produced in proton-antiproton collisions at s**(1/2)=1.96 TeV

We search for the standard model Higgs boson produced in association with an electroweak vector boson in events with no identified charged leptons, large imbalance in transverse momentum, and two jets where at least one contains a secondary vertex consistent with the decay of b hadrons. We use ~1 fb-1 integrated luminosity of proton-antiproton collisions at s**(1/2)=1.96 TeV recorded by the CDF II experiment at the Tevatron. We find 268 (16) single (double) b-tagged candidate events, where 248 +/- 43 (14.4 +/- 2.7) are expected from standard model background processes. We place 95% confidence level upper limits on the Higgs boson production cross section for several Higgs boson masses ranging from 110 GeV/c2 to 140 GeV/c2. For a mass of 115 GeV/c2 the observed (expected) limit is 20.4 (14.2) times the standard model prediction.Comment: 8 pages, 2 figures, submitted to Phys. Rev. Let

Observation and Mass Measurement of the Baryon Ξb−\Xi^-_b

We report the observation and measurement of the mass of the bottom, strange baryon $\Xi^-_b$ through the decay chain $\Xi^-_b \to J/\psi \Xi^-$, where $J/\psi \to \mu^+ \mu^-$, $\Xi^- \to \Lambda \pi^-$, and $\Lambda \to p \pi^-$. Evidence for observation is based on a signal whose probability of arising from the estimated background is 6.6 x 10^{-15}, or 7.7 Gaussian standard deviations. The $\Xi^-_b$ mass is measured to be $5792.9\pm 2.5$ (stat.) $\pm 1.7$ (syst.) MeV/$c^2$.Comment: Minor text changes for the second version. Accepted by Phys. Rev. Let