The Loss Of Genomic Uracil Homeostasis And Aid-Dependent Accumulation Of Dna Damage In B Cell Lymphomas

Activation-induced deaminase (AID) is a sequence-selective DNA cytosine deaminase that introduces uracils in immunoglobulin genes. This DNA mutator is required for somatic hypermutation and class switch recombination- processes involved in the affinity maturation and diversification of antibodies. AID, however, can also lead to deleterious mutations and translocations promoting lymphomagenesis. The introduction of uracils throughout the genome of activated B cells and the ability of UNG2 glycosylase to excise these uracils is examined here. This interplay was also studied in cancerous B cells, with different results emerging in transformed cells versus healthy cells. Genomic uracil levels are found to remain at the same level in normal B cells stimulated to express AID. However the increase in uracils by 11- to 60- fold detected in stimulated B cells deficient in UNG, suggests that normal B cells do accumulate high levels of genomic uracils. However, these uracils are efficiently and effectively removed in UNG proficient cells, suggesting a balance or homeostasis between uracil creation and elimination. Interestingly, murine B cell cancer lines, human B cell cancer cell lines, and several human B cell patient tumors from several types of lymphomas overexpressing AID, were found to accumulate genomic uracils at levels comparable to those seen in activated UNG-/- B cells. These lymphoma/leukemia cells are not defective in uracil removal and express UNG2 gene at the same level in normal peripheral B cells or higher. In addition, they also have similar nuclear uracil excision activities suggesting uracils accumulate despite robust uracil excision capabilities. These results suggest that the homeostasis of uracil introduction and excision seen in normal stimulated B cells is disrupted in lymphomas overexpressing AID despite UNG2 expression and activity, resulting in the accumulation of high levels of genome wide uracils. The majority of human B cell lymphomas do in fact derive from cells that have undergone the germinal center reaction and are associated with the expression of AID. The high levels of uracils that accumulate in the genomes of B cell lymphomas suggests other types of DNA damage may also be present in an AID-dependent manner as the cell attempts to remove and repair these uracils. Here, we see that human B cell lymphoma cell lines that contain high uracil loads also accumulate elevated levels of other types of genome wide DNA damage dependent on AID. These include abasic sites and single- and double-strand breaks. In addition, the accumulation of DNA lesions reduces cell viability. These lesions are due in part to the attempted repair of uracils by uracil DNA glycosylase

A Search For The Sm Higgs Boson In The Process Zhllbb In 4.1/fb Of Cdf Ii Data

This dissertation presents a search for the standard model (SM) Higgs boson in the associated production process ZH → l+l- bb using 4.1fb-1 of Tevatron collision data collected with the CDF II detector. To increase the sensitivity to a ZH signal over previous CDF searches, we implement new electron and expanded b-jet identification algorithms. We utilize neural network classifiers enhanced with matrix element probabilities, a b-jet identifying neural network, and multivariate jet energy corrections to maximize the separation of signal from SM backgrounds. We employ three neural network classifiers separately optimized for each of our three b-tag categories. We find good agreement between the observed data and the predicted SM backgrounds. The neural network output for data is compared to the output for the expected SM background to set 95% confidence level upper limits on the ZH production cross section times the branching ratio for H→ bb. We consider Higgs boson masses between 100 and 150 GeV/c2 in 5 GeV steps. For a Higgs boson mass of 115 GeV/c2 we observe (expect) a 95% confidence level upper limit of 5.9(6.8)

Vibrational Sum Frequency Spectroscopic Investigation of the Azimuthal Anisotropy and Rotational Dynamics of Methyl-Terminated Silicon(111) Surfaces

Polarization-selected vibrational sum frequency generation spectroscopy (SFG) has been used to investigate the molecular orientation of methyl groups on CH_(3)-terminated Si(111) surfaces. The symmetric and asymmetric C–H stretch modes of the surface-bound methyl group were observed by SFG. Both methyl stretches showed a pronounced azimuthal anisotropy of the 3-fold symmetry in registry with the signal from the Si(111) substrate, indicating that the propeller-like rotation of the methyl groups was hindered at room temperature. The difference in the SFG line widths for the CH_3 asymmetric stretch that was observed for different polarization combinations (SPS and PPP for SFG, visible, and IR) indicated that the rotation proceeded on a 1–2 ps time scale, as compared to the 100 fs rotational dephasing of a free methyl rotor at room temperature

Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron

We study the underlying event in proton-antiproton collisions by examining the behavior of charged particles (transverse momentum pT > 0.5 GeV/c, pseudorapidity |\eta| < 1) produced in association with large transverse momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan production) or the leading jet (in high-pT jet production) in each event to define three regions of \eta-\phi space; toward, away, and transverse, where \phi is the azimuthal scattering angle. For Drell-Yan production (excluding the leptons) both the toward and transverse regions are very sensitive to the underlying event. In high-pT jet production the transverse region is very sensitive to the underlying event and is separated into a MAX and MIN transverse region, which helps separate the hard component (initial and final-state radiation) from the beam-beam remnant and multiple parton interaction components of the scattering. The data are corrected to the particle level to remove detector effects and are then compared with several QCD Monte-Carlo models. The goal of this analysis is to provide data that can be used to test and improve the QCD Monte-Carlo models of the underlying event that are used to simulate hadron-hadron collisions.Comment: 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

Shrinking a large dataset to identify variables associated with increased risk of Plasmodium falciparum infection in Western Kenya

Large datasets are often not amenable to analysis using traditional single-step approaches. Here, our general objective was to apply imputation techniques, principal component analysis (PCA), elastic net and generalized linear models to a large dataset in a systematic approach to extract the most meaningful predictors for a health outcome. We extracted predictors for Plasmodium falciparum infection, from a large covariate dataset while facing limited numbers of observations, using data from the People, Animals, and their Zoonoses (PAZ) project to demonstrate these techniques: data collected from 415 homesteads in western Kenya, contained over 1500 variables that describe the health, environment, and social factors of the humans, livestock, and the homesteads in which they reside. The wide, sparse dataset was simplified to 42 predictors of P. falciparum malaria infection and wealth rankings were produced for all homesteads. The 42 predictors make biological sense and are supported by previous studies. This systematic data-mining approach we used would make many large datasets more manageable and informative for decision-making processes and health policy prioritization

Combined search for the standard model Higgs boson decaying to a bb pair using the full CDF data set

We combine the results of searches for the standard model Higgs boson based on the full CDF Run II data set obtained from sqrt(s) = 1.96 TeV p-pbar collisions at the Fermilab Tevatron corresponding to an integrated luminosity of 9.45/fb. The searches are conducted for Higgs bosons that are produced in association with a W or Z boson, have masses in the range 90-150 GeV/c^2, and decay into bb pairs. An excess of data is present that is inconsistent with the background prediction at the level of 2.5 standard deviations (the most significant local excess is 2.7 standard deviations).Comment: To be published in Phys. Rev. Lett (v2 contains minor updates based on comments from PRL

Observation of the Baryonic Flavor-Changing Neutral Current Decay Lambda_b -> Lambda mu+ mu-

We report the first observation of the baryonic flavor-changing neutral current decay Lambda_b -> Lambda mu+ mu- with 24 signal events and a statistical significance of 5.8 Gaussian standard deviations. This measurement uses ppbar collisions data sample corresponding to 6.8fb-1 at sqrt{s}=1.96TeV collected by the CDF II detector at the Tevatron collider. The total and differential branching ratios for Lambda_b -> Lambda mu+ mu- are measured. We find B(Lambda_b -> Lambda mu+ mu-) = [1.73+-0.42(stat)+-0.55(syst)] x 10^{-6}. We also report the first measurement of the differential branching ratio of B_s -> phi mu+ mu- using 49 signal events. In addition, we report branching ratios for B+ -> K+ mu+ mu-, B0 -> K0 mu+ mu-, and B -> K*(892) mu+ mu- decays.Comment: 8 pages, 2 figures, 4 tables. Submitted to Phys. Rev. Let

Observation of Exclusive Gamma Gamma Production in p pbar Collisions at sqrt{s}=1.96 TeV

We have observed exclusive \gamma\gamma production in proton-antiproton collisions at \sqrt{s}=1.96 TeV, using data from 1.11 \pm 0.07 fb^{-1} integrated luminosity taken by the Run II Collider Detector at Fermilab. We selected events with two electromagnetic showers, each with transverse energy E_T > 2.5 GeV and pseudorapidity |\eta| < 1.0, with no other particles detected in -7.4 < \eta < +7.4. The two showers have similar E_T and azimuthal angle separation \Delta\phi \sim \pi; 34 events have two charged particle tracks, consistent with the QED process p \bar{p} to p + e^+e^- + \bar{p} by two-photon exchange, while 43 events have no charged tracks. The number of these events that are exclusive \pi^0\pi^0 is consistent with zero and is < 15 at 95% C.L. The cross section for p\bar{p} to p+\gamma\gamma+\bar{p} with |\eta(\gamma)| < 1.0 and E_T(\gamma) > 2.5$ GeV is 2.48^{+0.40}_{-0.35}(stat)^{+0.40}_{-0.51}(syst) pb.Comment: 7 pages, 4 figure