Simultaneously quantifying parent drugs and screening for metabolites in plasma pharmacokinetic samples using selected reaction monitoring information-dependent acquisition on a QTrap instrument

Bioanalytical support of plasma pharmacokinetic (PK) studies for drug discovery programs primarily involves the quantitative analysis of dosed compounds using liquid chromatography/atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) operated in selected reaction monitoring (SRM) mode. However, there is a growing need for information on the metabolism of new chemical entities (NCEs), in addition to the time-concentration profiles from these studies. In this paper, we present a novel approach to not only quantify parent drugs with SRM, but also simultaneously screen for metabolites using a hybrid triple quadrupole/linear ion trap (QqQ(LIT)) instrument. This was achieved by incorporating both the conventional SRM-only acquisition of parent compounds and the SRM-triggered information-dependent acquisition (IDA) of potential metabolites within the same scan cycle during the same LC/MS/MS run. Two test compounds were used to demonstrate the applicability of this approach. Plasma samples from PK studies were processed by simple protein precipitation and the supernatant was diluted with water before injection. The fast scanning capability of the linear ion trap allowed for the information-dependent acquisition of metabolite MS/MS spectra (<1 s/scan), in addition to the collection of adequate data points for SRM-only channels. The MS/MS spectra obtained from potential metabolites in post-dose samples correlated well with the spectra of the parent compounds studied, therefore providing additional confirmatory structure information without the need for repetitive analyses. Relative quantitative time-concentration profiles of identified metabolites were also obtained. Furthermore, this articulated SRM+SRM-IDA approach generated equivalent quantitative results for parent compounds to those obtained by conventional SRM-only analysis. This approach has been successfully used to support discovery PK screening programs.     

Imprinted diffractive optics for terahertz radiation

Terahertz diffractive optic elements have been fabricated in polypropylene by imprinting with a silicon master. A silicon master is created with eight phase levels for high diffraction efficiency and etched using inductively coupled plasma reactive ion etching. This technique enables the rapid replication of complex optical structures in a high transmission material. Excellent replication of multilevel high efficiency Fresnel lenses is shown. The resulting lenses were tested with a 2 THz quantum cascade laser. The signal strength at the focus was 70 times the base signal strength.     

Hamilton-Jacobi expansion of the scattering amplitude

The calculation of the scattering amplitude is reduced to the problem of solving a set of classical Hamilton-Jacobi equations. This allows one to incorporate classical intuition into approximations at a fundamental level. The result is actually an iterative expansion for the scattering amplitude which is expected to be convergent in the high-energy limit. The first term in the expansion is shown to be the Glauber approximation, which is an approximation used extensively in nuclear as well as atomic and particle physics.     

Study of Zgamma events and limits on anomalous ZZgamma and Zgammagamma couplings in pp collisions at square root s = 1.96 TeV

We present a measurement of the Zgamma production cross section and limits on anomalous ZZgamma and Zgammagamma couplings for form-factor scales of lambda = 750 and 1000 GeV. The measurement is based on 138 (152) candidates in the eegamma (mumugamma) final state using 320(290) pb(-1) of pp(-1) collisions at square root of s = 1.96 TeV. The 95% C.L. limits on real and imaginary parts of individual anomalous couplings are /h(10,30)Z/ < 0.23, /h(20,40)Z/ < 0.020, /h(10,30)gamma/ < 0.23, and /h(20,40)gamma/ < 0.019 for lambda = 1000 GeV.     

Measurement of the Lambda0b lifetime in the decay lambda0b--> J/psiLambda0 with the D0 detector

We present measurements of the Lambda(0)(b) lifetime in the exclusive decay channel Lambda(0)(b)--> J/psiLambda(0), with J/psi--> mu(+)mu(-) and Lambda(0)--> ppi(-), the B0 lifetime in the decay B0-->J/psiK(0)(S) with J/psi--> mu(+)mu(-) and K(0)(S)-->pi(+)pi(-), and the ratio of these lifetimes. The analysis is based on approximately 250 pb(-1) of data recorded with the D0 detector in pp collisions at sqrt[s] = 1.96 TeV. The Lambda(0)(b) lifetime is determined to be tau(Lambda(0)(b)) = 1.22(+0.22)(-0.18)(stat) +/- 0.04(syst) ps, the B0 lifetime tau(B0) = 1.40(+0.11)(-0.10)(stat) +/- 0.03(syst) ps, and the ratio tau(Lambda(0)(b))/tau(B0) = 0.87(+0.17)(-0.14)(stat) +/- 0.03(syst). In contrast with previous measurements using semileptonic decays, this is the first determination of the Lambda(0)(b) lifetime based on a fully reconstructed decay channel.     

Measurement of the lifetime difference in the B0(s) system

We present a study of the decay B0(s) --> J/psiphi. We obtain the CP-odd fraction in the final state at time zero, Rperpendicular = 0.16 +/- 0.10(stat) +/- 0.02 (syst), the average lifetime of the (B0(s), B0(s)) system, tau(B0(s)) = 1.39(+0.13)(-0.16)(stat)(+0.01)(-0.02)(syst) ps, and the relative width difference between the heavy and light mass eigenstates, DeltaGamma/Gamma tripple bond (GammaL - GammaH)/Gamma = 0.24(+0.28)(-0.38)(stat)(+0.03)(-0.04)(syst). With the additional constraint from the world average of the lifetime measurements using semileptonic decays, we find tau(B0(s)) = 1.39 +/- 0.06 ps and DeltaGamma/Gamma = 0.25(+0.14)(-0.15). For the ratio of the B0(s) and B0 lifetimes we obtain tau(B0(s))/tau(B0) = 0.91 +/- 0.09(stat) +/- 0.003(syst).     

Search for supersymmetry via associated production of charginos and neutralinos in final states with three leptons

A search for associated production of charginos and neutralinos is performed using data recorded with the D0 detector at a pp center-of-mass energy of 1.96 TeV at the Fermilab Tevatron Collider. This analysis considers final states with missing transverse energy and three charged leptons, of which at least two are electrons or muons. No evidence for supersymmetry is found in a data set corresponding to an integrated luminosity of 320 pb-1. Limits on the product of the production cross section and leptonic branching fraction are set. For the minimal supergravity model, a chargino lower mass limit of 117 GeV at the 95% C.L. is derived in regions of parameter space with enhanced leptonic branching fractions.     

Search for Randall-Sundrum gravitons in dilepton and diphoton final states

We report the first direct search for the Kaluza-Klein (KK) modes of Randall-Sundrum gravitons using dielectron, dimuon, and diphoton events observed with the D0 detector operating at the Fermilab Tevatron pp(-) Collider at sqrt[s]=1.96 TeV. No evidence for resonant production of gravitons has been found in the data corresponding to an integrated luminosity of approximately equal to 260 pb(-1). Lower limits on the mass of the first KK mode at the 95% C.L. have been set between 250 and 785 GeV, depending on its coupling to standard model particles.