Observation of the decay B- → D(s)((*)+) K- ℓ- ν(ℓ).

We report the observation of the decay B- → D(s)((*)+) K- ℓ- ν(ℓ) based on 342 fb(-1) of data collected at the Υ(4S) resonance with the BABAR detector at the PEP-II e+ e- storage rings at SLAC. A simultaneous fit to three D(s)(+) decay chains is performed to extract the signal yield from measurements of the squared missing mass in the B meson decay. We observe the decay B- → D(s)((*)+) K- ℓ- ν(ℓ) with a significance greater than 5 standard deviations (including systematic uncertainties) and measure its branching fraction to be B(B- → D(s)((*)+) K- ℓ- ν(ℓ)) = [6.13(-1.03)(+1.04)(stat)±0.43(syst)±0.51(B(D(s)))]×10(-4), where the last error reflects the limited knowledge of the D(s) branching fractions.

Test of lepton universality in Υ(1S) decays at BABAR.

The ratio R(τµ)(Υ(1S))=Γ(Υ(1S)→τ+ τ-)/Γ(Υ(1S)→µ+ µ-) is measured using a sample of (121.8±1.2)×10(6)Υ(3S) events recorded by the BABAR detector. This measurement is intended as a test of lepton universality and as a search for a possible light pseudoscalar Higgs boson. In the standard model (SM) this ratio is expected to be close to 1. Any significant deviations would violate lepton universality and could be introduced by the coupling to a light pseudoscalar Higgs boson. The analysis studies the decays Υ(3S)→Υ(1S)π+ π-, Υ(1S)→l+ l-, where l=µ, τ. The result, R(τµ)(Υ(1S))=1.005±0.013(stat)±0.022(syst), shows no deviation from the expected SM value, while improving the precision with respect to previous measurements.

Evidence for direct CP violation in the measurement of the Cabbibo-Kobayashi-Maskawa angle γ with B∓ → D(*)K(*)∓ decays.

We report the measurement of the Cabibbo-Kobayashi-Maskawa CP-violating angle γ through a Dalitz plot analysis of neutral D-meson decays to K(S)(0) π+ π- and K(S)(0) K+ K- produced in the processes B∓ → DK∓, B∓ D* K∓ with D* → Dπ(0), Dγ, and B∓ → DK*∓ with K*∓ → K(S)(0) π∓, using 468 million BB pairs collected by the BABAR detector at the PEP-II asymmetric-energy e+ e- collider at SLAC. We measure γ = (68 ± 14 ± 4 ± 3)° (modulo 180°), where the first error is statistical, the second is the experimental systematic uncertainty, and the third reflects the uncertainty in the description of the neutral D decay amplitudes. This result is inconsistent with γ = 0 (no direct CP violation) with a significance of 3.5 standard deviations.

Measurement of D0-D0 mixing parameters using D0 → K(S)(0)π+ π- and D0 → K(S)(0)K+ K- decays.

We report a direct measurement of D0-D0 mixing parameters through a time-dependent amplitude analysis of the Dalitz plots of D(0) → K(S)(0) π+ π- and, for the first time, D0 → K(S)(0)K+ K- decays. The low-momentum pion π(s)(+) in the decay D*+ → D0 π(s)(+) identifies the flavor of the neutral D meson at its production. Using 468.5 fb(-1) of e+ e- colliding-beam data recorded near square root(s)=10.6 GeV by the BABAR detector at the PEP-II asymmetric-energy collider at SLAC, we measure the mixing parameters x = [1.6 ± 2.3(stat) ± 1.2(syst) ± 0.8(model)] × 10(-3), and y = [5.7 ± 2.0(stat) ± 1.3(syst) ± 0.7(model)] × 10(-3). These results provide the best measurement to date of x and y. The knowledge of the value of x, in particular, is crucial for understanding the origin of mixing.

Search for charged lepton flavor violation in narrow upsilon decays.

Charged-lepton flavor-violating processes are unobservable in the standard model, but they are predicted to be enhanced in several extensions to the standard model, including supersymmetry and models with leptoquarks or compositeness. We present a search for such processes in a sample of 99x10(6)Upsilon(2S) decays and 117x10(6)Upsilon(3S) decays collected with the BABAR detector. We place upper limits on the branching fractions B(Upsilon(nS)-->e(+/-)tau(-/+)) and B(Upsilon(nS)-->mu(+/-)tau(-/+)) (n=2,3) at the 10(-6) level and use these results to place lower limits of order 1 TeV on the mass scale of charged-lepton flavor-violating effective operators.

Searches for Lepton flavor violation in the decays tau{+/-}-->e{+/-}gamma and tau{+/-}-->mu{+/-}gamma.

Searches for lepton-flavor-violating decays of a tau lepton to a lighter mass lepton and a photon have been performed with the entire data set of (963+/-7)x10{6} tau decays collected by the BABAR detector near the Upsilon(4S), Upsilon(3S) and Upsilon(2S) resonances. The searches yield no evidence of signals and we set upper limits on the branching fractions of B(tau{+/-}-->e{+/-}gamma)<3.3x10{-8} and B(tau{+/-}-->mu{+/-}gamma)<4.4x10{-8} at 90% confidence level.

Search for f(J)(2220) in radiative J/ψ decays.

We present a search for f(J)(2220) production in radiative J/ψ→γf(J)(2220) decays using 460 fb⁻¹ of data collected with the BABAR detector at the SLAC PEP-II e(+)e⁻ collider. The f(J)(2220) is searched for in the decays to K(+)K⁻ and K(S)°K(S)°. No evidence of this resonance is observed, and 90% confidence level upper limits on the product of the branching fractions for J/ψ→γf(J)(2220) and f(J)(2220)→K(+)K⁻(K(S)°K(S)°) as a function of spin and helicity are set at the level of 10⁻5, below the central values reported by the Mark III experiment.

Precise measurement of the e+e- --> pi+pi-(gamma) cross section with the initial state radiation method at BABAR.

A precise measurement of the cross section of the process e(+)e(-) --> pi(+)pi(-)(gamma) from threshold to an energy of 3 GeV is obtained with the initial state radiation (ISR) method using 232 fb(-1) of data collected with the BABAR detector at e(+)e(-) center-of-mass energies near 10.6 GeV. The ISR luminosity is determined from a study of the leptonic process e(+)e(-) --> mu(+)mu(-)gamma(gamma). The leading-order hadronic contribution to the muon magnetic anomaly calculated using the pipi cross section measured from threshold to 1.8 GeV is (514.1 +/- 2.2(stat) +/- 3.1(syst)) x 10(-10).

Search for invisible decays of the Upsilon(1S).

We search for invisible decays of the Upsilon(1S) meson using a sample of 91.4 x 10(6) Upsilon(3S) mesons collected at the BABAR/PEP-II B factory. We select events containing the decay Upsilon(3S) --> pi(+)pi(-)Upsilon(1S) and search for evidence of an undetectable Upsilon(1S) decay recoiling against the dipion system. We set an upper limit on the branching fraction B(Upsilon(1S) --> invisible) < 3.0 x 10(-4) at the 90% confidence level.

Substituent effects on the genotoxicity of 4-nitrostilbene derivatives.

4-Nitrostilbene and twelve of its derivatives (eleven E-stilbenes and two Z-stilbenes) were examined for possible quantitative structure-activity relationships of their in vitro and in vivo genotoxicity. Relative mutagenicity was studied with and without S9 activation in Salmonella strains TA98 and TA100, as well as in the nitroreductase deficient strains TA98/NR and TA100/NR. Chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of the nitrostilbenes were observed as an indicator of in vivo genotoxicity. All of the compounds were active in TA98 and TA100 without S9 activation, with the exception of 4-amino-4'-nitrostilbene in TA100. Mutagenic activity was greatly reduced or eliminated in the NR strains, which is consistent with metabolic activation of the compounds by bacterial reductase. The presence of S9 lowered the activity of most of the nitrostilbenes presumedly by enzymatic detoxication. Hammet values of substituents, partition coefficients and frontier orbital energies (ELUMO and EHOMO) were studied for correlations with mutagenicity of the eleven E-stilbenes. Correlations could be established between mutagenicity in TA98 without S9 activation and the Hammet values. The same mutagenicity could also be correlated to ELUMO. Rationales for these correlations include the concept that electron-withdrawing groups which lower ELUMO should facilitate the reduction of the nitro group, leading to the proximate mutagen hydroxylamine. The correlations are also explained by the concept that electron-withdrawing groups should help stabilize the hydroxylamine intermediate and make the ultimate mutagenic species, the nitrenium ions, more reactive toward DNA. The relationship between mutagenicity and electronic effects of substituent groups found in vitro could not be extended to the in vivo results. However, except for the dinitrostilbenes, where insolubility prevented their testing, all the nitrostilbenes produced a statistically significant increase in chromosomal aberrations compared to the negative solvent control.

Substituent effects on the in vitro and in vivo genotoxicity of 4-aminobiphenyl and 4-aminostilbene derivatives.

4-Amino-4'-substituted biphenyls and 4-aminostilbenes substituted in the 3' or 4' position were studied for their in vitro and in vivo genotoxicity. The in vitro mutagenicity of the biphenyls with and without S9 activation was established with Salmonella strains TA98 and TA100 and that of the stilbenes with the same strains plus TA98/1,8-DNP6. The in vivo genotoxicity assay with both series of compounds was for chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of the chemicals. Hammett values of substituents, partition coefficients and frontier orbital energies (ELUMO and EHOMO) of the compounds were used for correlations with mutagenicity. The Salmonella mutagenicity in TA98 and TA98/1,8-DNP6 with S9 was correlated to Hammett sigma + values for the 4-aminostilbene substituents, showing a strong trend of increasing mutagenicity with an increase in the electron-withdrawing capability of the substituent. Hydrophobicity of the stilbenes, however, had little effect on their relative mutagenicity. The 4-aminobiphenyls showed a correlation between their mutagenicity and Hammett sigma + values of their 4'-substituents in stain TA98 with S9, although the trend was not as strong as for the stilbenes. But unlike the stilbenes, TA98 mutagenicity of the biphenyls could also be correlated to hydrophobicity, and structure-activity correlations for the biphenyls was substantially improved when both sigma + and hydrophobicity data were included. For strain TA100 with S9, little correlation was found between mutagenicity of the stilbenes and any of the parameters. However, a limited correlation did exist between the mutagenicity of the biphenyls and their hydrophobicity. There was also limited correlations of the mutagenicity for the stilbenes in TA98 and TA98/1,8-DNP6 with S9 to ELUMO or EHOMO. The in vivo genotoxicity results for the biphenyls and stilbenes could not be correlated to electronic effects as for the in vitro results, nor could they be explained by hydrophobicity. However, it is interesting to note that 3'-substituted 4-aminostilbenes were all substantially more genotoxic in vivo than their corresponding 4'-substituted counterparts. The most genotoxic compound in vivo in either series was 4-aminostilbene which would not have been predicted from the in vitro results.

Chromosomal aberrations in mouse lymphocytes exposed in vitro and in vivo to benzidine and 5 related aromatic amines.

Mouse lymphocytes were exposed in vitro for 2 h or in vivo for 24 h to benzidine and related aromatic amines to test for chromosome aberrations (CA) and mitotic indices. Uninduced mouse S9 was used to activate the amines for the in vitro tests to be consistent with the in vivo tests. Contrary to a previous report, no difference could be established in the genotoxicity of benzidine following activation with uninduced S9 compared to induced S9. There were concentration related increases in CA for benzidine and all the amines in vitro except for 4,4'-diaminostilbene which exhibited the greatest cellular toxicity towards cultured lymphocytes. Benzidine and its derivatives showed significant increases in CA in vivo compared to its negative control. The CA values for 4-aminostilbene were significantly higher than the other amines in both in vivo and in vitro studies. These genotoxicity results for 4-aminostilbene are consistent with our previous report of the pronounced CA effects in murine bone-marrow cells but would not be predicted from Salmonella mutagenicity tests.

ortho-Substituent effects on the in vitro and in vivo genotoxicity of benzidine derivatives.

Benzidine and its 3,3'-diamino, 3,3'-dimethyl, 3,3'-dimethoxy, 3,3'-difluoro, 3,3'-dichloro, 3,3'-dibromo, 3,3'-dicarbomethoxy and 3,3'-dinitro derivatives together with 2-nitrobenzidine and 3-nitrobenzidine were compared for their in vitro and in vivo genotoxicity. Relative mutagenicity was established with Salmonella strains TA98, TA98/1,8-DNP6 and TA100 with and without S9 activation. All the derivatives in the presence of S9 were more mutagenic than benzidine with 3,3'-dinitro- and 3-nitro-benzidine having the greatest mutagenicity. Mutagenicity in all 3 strains with S9 activation could be correlated to electron-withdrawing ability of substituent groups, as measured by the basicity of the amines. This correlation was explained on the basis that electron-withdrawing groups could favor the stability of the mutagenic intermediate N-hydroxylamine and also enhance the reactivity of the ultimate mutagenic species, the nitrenium ion. Mutagenicity was also correlated to the energy of the lowest unoccupied molecular orbitals (ELUMO). Hydrophobicity was found to have very limited effect on the relative mutagenicity of our benzidine derivatives. The in vivo endpoint was chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of benzidine and its derivatives. In contrast to the in vitro results, while all the amines were genotoxic in vivo, only the 3-nitro derivative had a significant increase in toxicity over benzidine.

Quantitative structure-activity relationships for the mutagenicity of propylene oxides with Salmonella.

A quantitative structure-activity relationship approach was used to investigate the mutagenicity of a series of seventeen-monosubstituted propylene oxides in Salmonella typhimurium strains TA100 and TA1535. Mutagenicity in strain TA100, using a liquid suspension assay, was found to correlate with chemical reactivity, as measured by the rates of reaction with two model bionucleophiles, nicotinamide and 4-(4-nitrobenzyl)pyridine. However, since the reactivity of three of the epoxides did not correlate to their Taft sigma * values, as a measure of the electronic effects of substituent groups, neither was their mutagenicity predicted by this substituent constant. The relative mutagenicity for the propylene oxides was different in the liquid suspension assay than that determined by the standard plate incorporation assay and also differed between the two bacterial strains. The assay differences were attributed to epoxide stability. The differences between strains was observed to be due to the response of the error-prone repair system, found only in TA100, to the stronger alkylating agents.

Base-pair mutations caused by six aliphatic epoxides in Salmonella typhimurium TA100, TA104, TA4001, and TA4006.

Salmonella typhimurium strains TA100, TA104, TA4001, and TA4006 were used to detect the base-pair mutations caused by six aliphatic epoxides: chloropropylene oxide, glycidyl 1-naphthyl ether, glycidyl 4-nitrophenyl ether, 1-naphthyl-propylene oxide, styrene oxide, and trichloropropylene oxide. Dose-mutagenicity relationships could be established for all six epoxides in strains TA100 and TA104 but not in strains TA4001 and TA4006. These results, together with the lack of sensitivity of the TA100 revertants to DL-1,2,4-triazole-3-alanine, indicate CG-->TA transitions and/or CG-->AT transversions are of major importance for mutations induced by these epoxides in Salmonella TA100 and possibly TA104. In addition, since the reproducibility of the effect of the triazole on TA104 reversions was poor, TA-->AT transversions were not eliminated as also contributing to the mutagenicity of these epoxides in this Salmonella strain.

The genotoxicity of enantiomeric aliphatic epoxides.

The (R)- and (S)-optical isomers of 9 epoxides, benzyloxymethyloxirane, epichlorohydrin, glycidol, glycidyl 3-nitrobenzenesulfonate, glycidyl 4-nitrobenzoate, glycidyl tosylate, styrene oxide, glycidyl 1-naphthyl ether and glycidyl 4-nitrophenyl ether, have been compared for their in vivo and in vitro genotoxicity. The in vitro short-term test employed was the Ames mutagenicity assay with Salmonella strain TA100. The in vivo tests were chromosomal aberrations (CA) as well as sister-chromatid exchange (SCE) in bone-marrow cells of mice following intraperitoneal administration of these epoxides. Differences in mutagenicity between isomers were established with TA100 for all the compounds. While 13 of the isomers were genotoxic compared to a negative control by CA measurements, only in the case of glycidyl 4-nitrobenzoate could a significant difference be found between isomers by this test. However, with SCE evaluations, differences were detected between the (R)- and (S)-isomers for all the pairs of compounds with the exception of those for benzyloxymethyloxirane and glycidyl 4-nitrophenyl ether. At least in part, differences in the patterns of genotoxicity among compounds can be related to their differences in reaction pathways.

The in vivo and in vitro genotoxicity of aromatic amines in relationship to the genotoxicity of benzidine.

Benzidine and 12 related aromatic amines have been studied for the effects of substituent groups and pi orbital conjugation on their genotoxicity as measured by their mutagenicity in vitro with Salmonella and by chromosomal aberrations (CA) in vivo in the bone-marrow cells of mice. The in vitro studies indicated increases in mutagenicity with increases in the electron withdrawing ability of para' substituents. Mutagenicity also increases with increased conjugation as shown by the degree of planarity of the biphenyl compounds and by comparing the mutagenicities of biphenyl amines to stilbenes as well as to ethylene bridged diphenyl compounds. The relative in vitro mutagenicity results were not predictive of relative in vivo CA results. The 3 most genotoxic compounds in vivo were the conjugated amines without substituents in the para' position. The CA values for 4-aminostilbene were exceptionally high. These in vivo results indicate increased genotoxicity for benzidine analogs without substitution in the para' position.

Genotoxicity of chryseno[4,5-bcd]thiophene and its sulfone derivative.

Our recent syntheses of chryseno[4,5-bcd]thiophene together with its potential sulfone metabolite, chryseno[4,5-bcd]thiophene-4,4-dioxide, have made these compounds available for genotoxicity testing. Such toxicity testing is of interest as this thiophene is an isoster of the established carcinogen benzo[a]pyrene and is one of the thiaarenes which are potential environmental contaminants found in fossil fuels. Although the thiophene was less mutagenic than benzo[a]pyrene in Salmonella strains TA98 and TA100 after S9 activation, it exhibited in vivo chromosomal aberration activity equal to that of benzo[a]pyrene in the bone-marrow cells of mice. A reduced activity with Salmonella as well as in the bone-marrow cell assay for the sulfone does not support its role as the key active metabolic intermediate for the genotoxicity of the thiophene. Our molecular orbital calculations would be consistent with the concept of activation through a diol-epoxide mechanism and offers an explanation for the reduced genotoxicity of the sulfone via this mechanism. These genotoxicity studies support the concern that sulfur isosters of established carcinogenic polycyclic aromatic hydrocarbons could themselves be toxic.

Mutagenicity in Salmonella and sister chromatid exchange in mice for 1,4-, 1,3-, 2,4-, and 3,4-dimethylphenanthrenes.

The mutagenicity in Salmonella and in vivo sister chromatid exchange in the bone-marrow cells of mice was determined for 1,4-, 1,3-, 2,4-, and 3,4-dimethylphenanthrene (DMPh) with the objective to study the relative importance of substitution at the 1 and 4 positions of this series of methylated phenanthrenes. For both tests, 1,4- DMPh was decidedly more genotoxic than the remaining regioisomers. While the well recognized role of steric crowding in the bay region is a factor in this enhanced genotoxicity, equally important is substitution at the 1 position with its potential to inhibit detoxication through 9,10-diol formation.

DNA strand breaks in liver for four aliphatic epoxides in mice.

Four aliphatic epoxides, 1-naphthyl glycidyl ether (NGE), 1-naphthylpropylene oxide (NPO), 4-nitrophenyl glycidyl ether (NPGE), 3,3,3-trichloropropylene oxide (TCPO) and two of their precursors, 1-allylnaphthalene (AN) and 3,3,3-trichloropropylene (TCP), were selected for DNA strand-break analysis in liver in vivo with mice. The four epoxides selected were among the most mutagenic aliphatic epoxides in our previous structure-mutagenicity studies with the Ames test and had been evaluated for their in vivo genotoxicity as measured by sister-chromatid exchange (SCE) and chromosome aberrations (CA). A significant increase in the percentage of unwound DNA was observed at a 4-h exposure time for all the compounds at high doses except for AN. TCPO, the least genotoxic compound in bone marrow, had the greatest liver toxicity after 1-h exposure while NGE showed the most toxicity after 6 h. As might be expected from their corresponding epoxides, AN but not TCP exhibited significant SCE activity in the bone marrow of mice. This study reemphasizes the importance of evaluating the stability of direct-acting alkylating agents in comparing test results and in establishing the relative order of genotoxicity for such compounds.