MECHANISMS AND EFFECTS OF MITOCHONDRIAL DNA INSTABILITY AND COPY NUMBER MANIPULATION

Defects in mitochondrial DNA (mtDNA) maintenance cause a range of human diseases, including autosomal dominant progressive external ophthalmoplegia (adPEO). This study aimed to clarify the molecular background of adPEO. We discovered that deoxynucleoside triphosphate (dNTP) metabolism plays a crucial in mtDNA maintenance and were thus prompted to search for therapeutic strategies based on the modulation of cellular dNTP pools or mtDNA copy number. Human mtDNA is a 16.6 kb circular molecule present in hundreds to thousands of copies per cell. mtDNA is compacted into nucleoprotein clusters called nucleoids. mtDNA maintenance diseases result from defects in nuclear encoded proteins that maintain the mtDNA. These syndromes typically afflict highly differentiated, post-mitotic tissues such as muscle and nerve, but virtually any organ can be affected. adPEO is a disease where mtDNA molecules with large-scale deletions accumulate in patients tissues, particularly in skeletal muscle. Mutations in five nuclear genes, encoding the proteins ANT1, Twinkle, POLG, POLG2 and OPA1, have previously been shown to cause adPEO. Here, we studied a large North American pedigree with adPEO, and identified a novel heterozygous mutation in the gene RRM2B, which encodes the p53R2 subunit of the enzyme ribonucleotide reductase (RNR). RNR is the rate-limiting enzyme in dNTP biosynthesis, and is required both for nuclear and mitochondrial DNA replication. The mutation results in the expression of a truncated form of p53R2, which is likely to compete with the wild-type allele. A change in enzyme function leads to defective mtDNA replication due to altered dNTP pools. Therefore, RRM2B is a novel adPEO disease gene. The importance of adequate dNTP pools and RNR function for mtDNA maintenance has been established in many organisms. In yeast, induction of RNR has previously been shown to increase mtDNA copy number, and to rescue the phenotype caused by mutations in the yeast mtDNA polymerase. To further study the role of RNR in mammalian mtDNA maintenance, we used mice that broadly overexpress the RNR subunits Rrm1, Rrm2 or p53R2. Active RNR is a heterotetramer consisting of two large subunits (Rrm1) and two small subunits (either Rrm2 or p53R2). We also created bitransgenic mice that overexpress Rrm1 together with either Rrm2 or p53R2. In contrast to the previous findings in yeast, bitransgenic RNR overexpression led to mtDNA depletion in mouse skeletal muscle, without mtDNA deletions or point mutations. The mtDNA depletion was associated with imbalanced dNTP pools. Furthermore, the mRNA expression levels of Rrm1 and p53R2 were found to correlate with mtDNA copy number in two independent mouse models, suggesting nuclear-mitochondrial cross talk with regard to mtDNA copy number. We conclude that tight regulation of RNR is needed to prevent harmful alterations in the dNTP pool balance, which can lead to disordered mtDNA maintenance. Increasing the copy number of wild-type mtDNA has been suggested as a strategy for treating PEO and other mitochondrial diseases. Only two proteins are known to cause a robust increase in mtDNA copy number when overexpressed in mice; the mitochondrial transcription factor A (TFAM), and the mitochondrial replicative helicase Twinkle. We studied the mechanisms by which Twinkle and TFAM elevate mtDNA levels, and showed that Twinkle specifically implements mtDNA synthesis. Furthermore, both Twinkle and TFAM were found to increase mtDNA content per nucleoid. Increased mtDNA content in mouse tissues correlated with an age-related accumulation of mtDNA deletions, depletion of mitochondrial transcripts, and progressive respiratory dysfunction. Simultaneous overexpression of Twinkle and TFAM led to a further increase in the mtDNA content of nucleoids, and aggravated the respiratory deficiency. These results suggested that high mtDNA levels have detrimental long-term effects in mice. These data have to be considered when developing and evaluating treatment strategies for elevating mtDNA copy number.

Search for a Fermiophobic Higgs Boson Decaying into Diphotons in pp̅ Collisions at √s=1.96 TeV

A search for a narrow diphoton mass resonance is presented based on data from 3.0 fb^{-1} of integrated luminosity from p-bar p collisions at sqrt{s} = 1.96 TeV collected by the CDF experiment. No evidence of a resonance in the diphoton mass spectrum is observed, and upper limits are set on the cross section times branching fraction of the resonant state as a function of Higgs boson mass. The resulting limits exclude Higgs bosons with masses below 106 GeV at a 95% Bayesian credibility level (C.L.) for one fermiophobic benchmark model.

Search for WW and WZ production in lepton plus jets final state at CDF

We present a search for WW and WZ production in final states that contain a charged lepton (electron or muon) and at least two jets, produced in sqrt(s) = 1.96 TeV ppbar collisions at the Fermilab Tevatron, using data corresponding to 1.2 fb-1 of integrated luminosity collected with the CDF II detector. Diboson production in this decay channel has yet to be observed at hadron colliders due to the large single W plus jets background. An artificial neural network has been developed to increase signal sensitivity, as compared with an event selection based on conventional cuts. We set a 95% confidence level upper limit of sigma_{WW}* BR(W->lnu,W->jets)+ sigma_{WZ}*BR(W->lnu,Z->jets)

Search for Top-Quark Production via Flavor-Changing Neutral Currents in W+1 Jet Events at CDF

We report on the first search for top-quark production via flavor-changing neutral-current (FCNC) interactions in the non-standard-model process u(c)+g -> t using ppbar collision data collected by the CDF II detector. The data set corresponds to an integrated luminosity of 2.2/fb. The candidate events feature the signature of semileptonic top-quark decays and are classified as signal-like or background-like by an artificial neural network trained on simulated events. The observed discriminant distribution is in good agreement with the one predicted by the standard model and provides no evidence for FCNC top-quark production, resulting in a Bayesian upper limit on the production cross section sigma (u(c)+g -> t) u+g) c+g)

Search for Long-Lived Massive Charged Particles in 1.96 TeV pp̅ Collisions

We performed a signature-based search for long-lived charged massive particles (CHAMPs) produced in 1.0 $\rm{fb}^{-1}$ of $\bar{p}p$ collisions at $\sqrt{s}=1.96$ TeV, collected with the CDF II detector using a high transverse-momentum ($p_T$) muon trigger. The search used time-of-flight to isolate slowly moving, high-$p_T$ particles. One event passed our selection cuts with an expected background of $1.9 \pm 0.2$ events. We set an upper bound on the production cross section, and, interpreting this result within the context of a stable scalar top quark model, set a lower limit on the particle mass of 249 GeV/$c^2$ at 95% C.L.

Search for High-Mass Resonances Decaying to Dimuons at CDF

We present a search for high-mass neutral resonances using dimuon data corresponding to an integrated luminosity of 2.3 fb$^{-1}$ collected in {$p\bar p$} collisions at {$\sqrt{s}$ = 1.96 TeV} by the CDF II detector at the Fermilab Tevatron. No significant excess above the standard model expectation is observed in the dimuon invariant-mass spectrum. We set 95% confidence level upper limits on $\sigma \cdot BR (p \bar{p} \to X \to \mu \bar{\mu})$, where $X$ is a boson with spin 0, 1, or 2. Using these cross section limits, we determine lower mass limits on sneutrinos in R-parity-violating supersymmetric models, $Z'$ bosons, and Kaluza-Klein gravitons in the Randall-Sundrum model.

Search for Gluino-Mediated Bottom Squark Production in pp̅ Collisions at √s=1.96 TeV

We report on a search for the supersymmetric partner of the bottom quark produced from gluino decays in data from 2.5 fb-1 of integrated luminosity collected by the Collider Detector at Fermilab at sqrt(s)=1.96 TeV. Candidate events are selected requiring two or more jets and large missing transverse energy. At least two of the jets are required to be tagged as originating from a b quark to enhance the sensitivity. The results are in good agreement with the prediction of the standard model processes, giving no evidence for gluino decay to sbottom quarks. This result constrains the gluino-pair-production cross section to be less than 40fb at 95% credibility level for a gluino mass of 350 GeV.

Search for Charged Higgs Bosons in Decays of Top Quarks in pp̅ Collisions at √s=1.96 TeV

We report the recent charged Higgs search in top quark decays in 2.2/fb CDF data. This is the first attempt to search for charged Higgs using fully reconstructed mass assuming H->c-sbar in small tan beta region. No evidence of a charged Higgs is observed in the CDF data, hence 95% upper limits are placed at B(t->H+b)

Search for Anomalous Production of Events with a Photon, Jet, b-quark Jet, and Missing Transverse Energy

We present a signature-based search for anomalous production of events containing a photon, two jets, of which at least one is identified as originating from a b quark, and missing transverse energy. The search uses data corresponding to 2.0/fb of integrated luminosity from p-pbar collisions at a center-of-mass energy of sqrt(s)=1.96 TeV, collected with the CDF II detector at the Fermilab Tevatron. From 6,697,466 events with a photon candidate with transverse energy ET> 25 GeV, we find 617 events with missing transverse energy > 25 GeV and two or more jets with ET> 15 GeV, at least one identified as originating from a b quark, versus an expectation of 607+- 113 events. Increasing the requirement on missing transverse energy to 50 GeV, we find 28 events versus an expectation of 30+-11 events. We find no indications of non-standard-model phenomena.

Search for standard model Higgs boson production in association with a W boson using a neural network discriminant at CDF

We present a search for standard model Higgs boson production in association with a W boson in proton-antiproton collisions at a center of mass energy of 1.96 TeV. The search employs data collected with the CDF II detector that correspond to an integrated luminosity of approximately 1.9 inverse fb. We select events consistent with a signature of a single charged lepton, missing transverse energy, and two jets. Jets corresponding to bottom quarks are identified with a secondary vertex tagging method, a jet probability tagging method, and a neural network filter. We use kinematic information in an artificial neural network to improve discrimination between signal and background compared to previous analyses. The observed number of events and the neural network output distributions are consistent with the standard model background expectations, and we set 95% confidence level upper limits on the production cross section times branching fraction ranging from 1.2 to 1.1 pb or 7.5 to 102 times the standard model expectation for Higgs boson masses from 110 to $150 GeV/c^2, respectively.

Search for narrow resonances lighter than ϒ mesons

We report a search for narrow resonances, produced in $p\bar{p}$ collisions at $\sqrt{s}=1.96$ TeV, that decay into muon pairs with invariant mass between 6.3 and 9.0 GeV/c^2. The data, collected with the CDF~II detector at the Fermilab Tevatron collider, correspond to an integrated luminosity of 630 pb$^{-1}$. We use the dimuon invariant mass distribution to set 90% upper credible limits of about 1% to the ratio of the production cross section times muonic branching fraction of possible narrow resonances to that of the $\Upsilon(1{\rm S})$ meson.

Search for the Production of Narrow tb̅ Resonances in 1.9 fb-1 of pp̅ Collisions at √s=1.96 TeV

We present new limits on resonant tb production in proton-antiproton collisions at 1.96 TeV, using 1.9 fb^-1 of data recorded with the CDF II detector at the Fermilab Tevatron. We reconstruct a candidate mass in events with a lepton, neutrino candidate, and two or three jets, and search for anomalous tb production as modeled by W'->tb. We set a new limit on a right-handed W' with standard model-like coupling, excluding any mass below 800 GeV at 95% C.L. The cross-section for any narrow, resonant tb production between 750 and 950 GeV is found to be less than 0.28 pb at 95% C.L. We also present an exclusion of the W' coupling strength versus W' mass over the range 300 to 950 GeV.

Updated search for the flavor-changing neutral-current decay D0→μ+μ- in pp̅ collisions at √s=1.96 TeV

We report on a search for the flavor-changing neutral-current decay D0 \to {\mu}+ {\mu}- in pp collisions at \surd s = 1.96 TeV using 360 pb-1 of integrated luminosity collected by the CDF II detector at the Fermilab Tevatron collider. A displaced vertex trigger selects long-lived D0 candidates in the {\mu}+ {\mu}-, {\pi}+{\pi}-, and K-{\pi}+ decay modes. We use the Cabibbo-favored D0 \to K-{\pi}+ channel to optimize the selection criteria in an unbiased manner, and the kinematically similar D0 \to{\pi}+ {\pi}- channel for normalization. We set an upper limit on the branching fraction (D0 --> {\mu}+ {\mu}-)

Improved Search for a Higgs Boson Produced in Association with Z→l+l- in pp̅ Collisions at √s=1.96 TeV

We present a search for the standard model Higgs boson produced with a Z boson in 4.1 fb^-1 of data collected with the CDF II detector at the Tevatron. In events consistent with the decay of the Higgs boson to a bottom-quark pair and the Z boson to electrons or muons, we set 95% credibility level upper limits on the ZH production cross section times the H -> b bbar branching ratio. Improved analysis methods enhance signal sensitivity by 20% relative to previous searches beyond the gain due to the larger data sample. At a Higgs boson mass of 115 GeV/c^2 we set a limit of 5.9 times the standard model value.

Search for Anomalous Production of Events with Two Photons and Additional Energetic Objects at CDF

We present results of a search for anomalous production of two photons together with an electron, muon, $\tau$ lepton, missing transverse energy, or jets using $p\bar{p}$ collision data from 1.1-2.0 fb$^{-1}$ of integrated luminosity collected by the Collider Detector at Fermilab (CDF). The event yields and kinematic distributions are examined for signs of new physics without favoring a specific model of new physics. The results are consistent with the standard model expectations. The search employs several new analysis techniques that significantly reduce instrumental backgrounds in channels with an electron and missing transverse energy.