Search for charmless B --> VV decays.

We have studied two-body charmless decays of the B meson into the final states rho(0)rho(0), K(*0)rho(0), K(*0)K(*0), K(*0)K(*0), K(*+)rho(0), K(*+)K(*0), and K(*+)K(*-) using only decay modes with charged daughter particles. Using 9.7x10(6) BB pairs collected with the CLEO detector, we place 90% confidence level upper limits on the branching fractions (1.4-14.1)x10(-5), depending on final state and polarization.

Hadronic mass moments in inclusive semileptonic B meson decays.

We have measured the first and second moments of the hadronic mass-squared distribution in B-->X(c)l nu, for P(lepton)>1.5 GeV/c. We find = 0.251+/-0.066 GeV(2), <(M(2)(X)-)(2)> = 0.576+/-0.170 GeV(4), where M macro(D) is the spin-averaged D meson mass. From that first moment and the first moment of the photon energy spectrum in b-->s gamma, we find the heavy quark effective theory parameter lambda(1) (in the modified minimal subtraction renormalization scheme, to order 1/M(3)(B) and beta(0)alpha(2)(s)) to be -0.24+/-0.11 GeV(2). Using these first moments and the B semileptonic width, and assuming parton-hadron duality, we obtain absolute value of V(cb) = 0.0404+/-0.0013.

Neutralizing antibodies associated with viremia control in a subset of individuals after treatment of acute human immunodeficiency virus type 1 infection.

Immediate treatment of acute human immunodeficiency virus type 1 (HIV-1) infection has been associated with subsequent control of viremia in a subset of patients after therapy cessation, but the immune responses contributing to control have not been fully defined. Here we examined neutralizing antibodies as a correlate of viremia control following treatment interruption in HIV-1-infected individuals in whom highly active antiretriviral therapy (HAART) was initiated during early seroconversion and who remained on therapy for 1 to 3 years. Immediately following treatment interruption, neutralizing antibodies were undetectable with T-cell-line adapted strains and the autologous primary HIV-1 isolate in seven of nine subjects. Env- and Gag-specific antibodies as measured by enzyme-linked immunosorbent assay were also low or undetectable at this time. Despite this apparent poor maturation of the virus-specific B-cell response during HAART, autologous neutralizing antibodies emerged rapidly and correlated with a spontaneous downregulation in rebound viremia following treatment interruption in three subjects. Control of rebound viremia was seen in other subjects in the absence of detectable neutralizing antibodies. The results indicate that virus-specific B-cell priming occurs despite the early institution of HAART, allowing rapid secondary neutralizing-antibody production following treatment interruption in a subset of individuals. Since early HAART limits viral diversification, we hypothesize that potent neutralizing-antibody responses to autologous virus are able to mature and that in some persons these responses contribute to the control of plasma viremia after treatment cessation.

Bounds on the CP asymmetry in b --> sgamma decays.

We have measured the CP asymmetry A(CP) identical with[gamma(b-->sgamma)-gammab-->sgamma)]/[gamma(b-->sgamma)+gamma(b-->sgamma)] to be A(CP) = (-0.079+/-0.108+/-0.022) (1.0+/-0.030), implying that, at 90% confidence level, A(CP) lies between -0.27 and +0.10. These limits rule out some extreme non-standard-model predictions, but are consistent with most, as well as with the standard model.

Observation of new states decaying into Lambda+(c)pi(-)pi(+).

Using 13.7 fb(-1) of data recorded by the CLEO detector at the Cornell Electron Storage Ring, we investigate the spectrum of charmed baryons which decay into Lambda+(c)pi(-)pi(+) and are more massive than the Lambda+(c)(2625) baryon. We find evidence for two new states: one is broad and has an invariant mass roughly 480 MeV above that of the Lambda+(c) baryon; the other is narrow with an invariant mass of 596+/-1+/-2 MeV above the Lambda+(c) mass.

Bounds on the CP asymmetry in like-sign dileptons from B(0)B*(0) meson decays.

We have measured the charge asymmetry in like-sign dilepton yields from B(0)B*(0) meson decays using the CLEO detector at the Cornell Electron Storage Ring. We find a(0)(ll) identical with[N(l(+)l(+))-N(l(-)l(-))]/[N(l(+)l(+))+N(l(-)l(-))] = +0.013+/-0.050+/-0.005. We combine this result with a previous, independent measurement and obtain Re(epsilon(B))/(1+ the absolute value of epsilon(B)(2)) = +0.0035+/-0.0103+/-0.0015 (uncertainties are statistical and systematic, respectively) for the CP impurity parameter, epsilon(B).

Evidence of New States Decaying into Xi(*)(c)pi.

Using 13.7 fb(-1) of data recorded by the CLEO detector at Cornell Electron Storage Ring, we report evidence of two new charmed baryons: one decaying into Xi(0')(c)pi(+) with the subsequent decay Xi(0')(c)-->Xi(0)(c)gamma, and its isospin partner decaying into Xi(+')(c)pi(-) followed by Xi(+')(c)-->Xi(+)(c)gamma. We measure the following mass differences for the two states: M(Xi(0)(c)gammapi(+))-M(Xi(0)(c)) = 318.2+/-1.3+/-2.9 MeV and M(Xi(+)(c)gammapi(-))-M(Xi(+)(c)) = 324.0+/-1.3+/-3.0 MeV. We interpret these new states as the J(P) = 1 / 2(-) Xi(c1) particles, the charmed-strange analogs of the Lambda(+)(c1)(2593).

Measurement of the lambda(+)(c) lifetime.

The Lambda+c lifetime is measured using 9.0 fb(-1) of e+e- annihilation data collected on or just below the Upsilon(4S) resonance with the CLEO II.V detector at CESR. Using an unbinned maximum likelihood fit, the Lambda+c lifetime is measured to be 179.6+/-6.9(stat)+/-4.4(syst) fs. The precision of this colliding beam measurement is comparable to other measurements, which are based on fixed-target experiments, with different systematic uncertainties.

Search for CP violation in B+/- --> J/psiK+/- and B+/- --> psi(2S)K+/- decays.

We present a search for direct CP violation in B+/--->J/psiK+/- and B+/--->psi(2S)K+/- decays. In a sample of 9.7x10(6) B&Bmacr; meson pairs collected with the CLEO detector, we have fully reconstructed 534 B+/--->J/psiK+/- and 120 B+/--->psi(2S)K+/- decays with very low background. We have measured the CP-violating charge asymmetry to be [+1.8+/-4.3(stat)+/-0.4(syst)]% for B+/--->J/psiK+/- and [+2.0+/-9. 1(stat)+/-1.0(syst)]% for B+/--->psi(2S)K+/-.

Development of a physiologically based pharmacokinetic model for hydroquinone.

Hydroquinone (HQ) produces nephrotoxicity and renal tubular adenomas in male F344 rats following 2 years of oral dosing. Female F344 and SD rats are comparatively resistant to these effects. Nephrotoxicity and tumorigenicity have been associated with a minor glutathione conjugation pathway following the oxidation of HQ to benzoquinone (BQ). The majority of administered doses (90-99%) consists of glucuronide and sulfate conjugates of HQ. An initial physiologically based pharmacokinetic model was developed to characterize the role of kinetics in the strain differences observed in HQ-induced renal toxicity and tumorigenicity. Partition coefficients, protein-binding, and metabolic rate constants were determined directly or estimated from a series of in vivo and in vitro studies. Metabolism was confined to the liver and GI tract. The total flux through the glutathione pathway represented the "internal dose" of HQ for nephrotoxicity. Simulations were compared to a variety of data from male and female F344 rats, male SD rats, and a single male human volunteer. Simulations of intraperitoneal administration resulted in higher amounts of glutathione conjugates than comparable oral doses. This was consistent with protein-binding and toxicity studies and emphasized the importance of first-pass GI tract metabolism. In addition, male F344 rats were predicted to form more total glutathione conjugates than SD rats at equivalent dose levels, which was also consistent with the observed strain differences in renal toxicity. This model represents the first stage in the development of a biologically based dose-response model for improving the scientific basis for human health risk assessments of HQ.

Human exposure to naturally occurring hydroquinone.

Hydroquinone (HQ) is a nonvolatile chemical used in the photographic, rubber, chemical, and cosmetic industries. HQ is also known to occur in nature as the beta-D-glucopyranoside conjugate (arbutin), and free HQ is a known component of cigarette smoke. Low concentrations of HQ have been detected in the urine and plasma of humans with no occupational or other known exposure to HQ. The studies reported here investigate dietary and other potential sources of HQ and their contribution to HQ concentrations in the plasma and urine of human volunteers. Analysis of possible food sources of HQ by GC indicated significant amounts of arbutin in wheat products (1-10 ppm), pears (4-15 ppm), and coffee and tea (0.1 ppm). Free HQ was found in coffee (0.2 ppm), red wine (0.5 ppm), wheat cereals (0.2-0.4 ppm), and broccoli (0.1 ppm). After consuming a meal including arbutin- and HQ-containing foods, volunteers showed significant increases in plasma and urinary levels of HQ and its conjugated metabolites (total HQ). Mean plasma concentrations of total HQ peaked at 5 times background levels at 2 h after the completion of the meal, and mean urinary excretion rates of total HQ peaked at 12 times background at 2-3 h after the meal. Immediately after smoking four cigarettes in approximately 30 min, mean plasma concentrations of total HQ were maximally 1.5 times background levels; mean urinary excretion rates of total HQ peaked at 2.5 times background at 1-3 h after smoking. These data indicate that considerable human exposure to HQ can result from plant-derived dietary sources and, to a lesser extent, from cigarette smoke.

New efficient sulfurizing reagents for the preparation of oligodeoxyribonucleotide phosphorothioate analogues.

A set of new sulfurizing agents representing disulfides of arylsulfonic acids has been developed for the automated synthesis of phosphorothioate oligonucleotide analogues via the phosphoramidite method. These reagents, such as bis(benzenesulfonyl)disulfide, bis(p-toluenesulfonyl)disulfide, bis(p-methoxybenzensulfonyl)disulfide, and bis (p-chlorobenzenesulfonyl) disulfide, are easily prepared crystalline solid compounds. They are relatively inexpensive, easy to handle, and efficiently convert internucleotide cyanoethyl phosphite to the phosphorothioate triester within 1-2 min. The efficiency of phosphorothioate oligonucleotide synthesis with the use of these reagents is comparable to that of phosphodiester oligonucleotides.

Use of phthaloyl protecting group for the automated synthesis of 3'-[(hydroxypropyl)amino] and 3'-[(hydroxypropyl)triglycyl] oligonucleotide conjugates.

The chemical stability of oligonucleotides (ODNs) containing 3'-propanolamine was investigated. Invariably, all the ODNs synthesized from Fmoc-protected 3-aminopropane-1,2-diol-CPG support gave a mixture of three compounds at the end of automated synthesis as analyzed by denaturing PAGE and HPLC. On the basis of analytical procedures, these compounds were identified to be 3'-[N-acetyl-N-(hydroxypropyl)amino],3'-[(hydroxypropyl)amino], and 3'-hydroxyl ODNs. The instability of the amino protecting group under the synthesis conditions was responsible for this observed heterogeneity. In order to evaluate the stability, a comparative study on the chemical stability of the ODN containing amino-protecting groups such as [(9-fluorenylmethyl)oxy]carbonyl (Fmoc), trifluoroacetyl (TFA), and phthaloyl was undertaken. The results indicate that the phthaloyl group provided the best stability for the synthesis of 3' amine-modified ODNs, and the protecting group is cleaved and deprotected in concentrated ammonium hydroxide:40% aqueous methylamine, 1:1, for 5-10 min, at 56 degrees C. The 3'-hydroxypropyl)triglycyl] ODN conjugates were also synthesized from Fmoc- and phthaloyl-protected (hydroxypropyl)triglycine-CPG supports.

Synthesis and properties of cholesteryl-modified triple-helix forming oligonucleotides containing a triglycyl linker.

In order to enhance the nuclear uptake of triple-helix forming oligonucleotides (TFOs), a triglycylcholesterol group was attached to the 3' end. The peptide unit was introduced as a "labile" linker with the aim of releasing the oligonucleotide from the endosomes by the action of peptidases after crossing the cell membrane. Cholesteryl-CPG (8) and -TentaGel (9) supports containing 2-[N-(glycylglycylglycyl)amino]propane-1,3-diol (GAP-3) linker were prepared and used for automated oligonucleotide synthesis. The synthesis, characterization, and stability of these compounds are described.