Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109769/1/cptclpt201378.pd

Dynamic interaction between WT1 and BASP1 in transcriptional regulation during differentiation

The Wilms’ tumour suppressor protein WT1 plays a central role in the development of the kidney and also other organs. WT1 can act as a transcription factor with highly context-specific activator and repressor functions. We previously identified Brain Acid Soluble Protein 1 (BASP1) as a transcriptional cosuppressor that can block the transcriptional activation function of WT1. WT1 and BASP1 are co-expressed during nephrogenesis and both proteins ultimately become restricted to the podocyte cells of the adult kidney. Here, we have analysed the WT1/BASP1 complex in a podocyte precursor cell line that can be induced to differentiate. Chromatin immunoprecipitation revealed that WT1 and BASP1 occupy the promoters of the Bak, c-myc and podocalyxin genes in podocyte precursor cells. During differentiation-dependent upregulation of podocalyxin expression BASP1 occupancy of the podocalyxin promoter is reduced compared to that of WT1. In contrast, the repressive WT1/BASP1 occupancy of the c-myc and Bak promoters is maintained and these genes are downregulated during the differentiation process. We provide evidence that the regulation of BASP1 promoter occupancy involves the sumoylation of BASP1. Our results reveal a dynamic cooperation between WT1 and BASP1 in the regulation of gene expression during differentiation

Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver

Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed

Opposite-side flavour tagging of B mesons at the LHCb experiment

The calibration and performance of the oppositeside flavour tagging algorithms used for the measurements of time-dependent asymmetries at the LHCb experiment are described. The algorithms have been developed using simulated events and optimized and calibrated with B + →J/ψK +, B0 →J/ψK ∗0 and B0 →D ∗− μ + νμ decay modes with 0.37 fb−1 of data collected in pp collisions at √ s = 7 TeV during the 2011 physics run. The oppositeside tagging power is determined in the B + → J/ψK + channel to be (2.10 ± 0.08 ± 0.24) %, where the first uncertainty is statistical and the second is systematic

Measurement of the ratio of branching fractions BR(B0 -> K*0 gamma)/BR(Bs0 -> phi gamma)

The ratio of branching fractions of the radiative B decays B0 -> K*0 gamma and Bs0 -> phi gamma has been measured using 0.37 fb-1 of pp collisions at a centre of mass energy of sqrt(s) = 7 TeV, collected by the LHCb experiment. The value obtained is BR(B0 -> K*0 gamma)/BR(Bs0 -> phi gamma) = 1.12 +/- 0.08 ^{+0.06}_{-0.04} ^{+0.09}_{-0.08}, where the first uncertainty is statistical, the second systematic and the third is associated to the ratio of fragmentation fractions fs/fd. Using the world average for BR(B0 -> K*0 gamma) = (4.33 +/- 0.15) x 10^{-5}, the branching fraction BR(Bs0 -> phi gamma) is measured to be (3.9 +/- 0.5) x 10^{-5}, which is the most precise measurement to date.Comment: 15 pages, 1 figure, 2 table

Measurements of the branching fractions of the decays B°s → D∓s K± and B°s → D¯sπ+

The decay mode B°s → D∓s K± allows for one of the theoretically cleanest measurements of the CKM angle γ through the study of time-dependent CP violation. This paper reports a measurement of its branching fraction relative to the Cabibbo-favoured mode B°s → D¯sπ+ based on a data sample corresponding to 0.37 fb¯¹ of proton-proton collisions at √s = 7TeV collected in 2011 with the LHCb detector. In addition, the ratio of B meson production fractions fs/fd, determined from semileptonic decays, together with the known branching fraction of the control channel B°s → D¯sπ+ is used to perform an absolute measurement of the branching fractions: B(B°s → D¯sπ+) = (2.95 ± 0.05 ± 0.17 -0.22 +0.18) × 10¯³ ; B(B°s → D∓s K±) = (1.90 ± 0.12 ± 0.13 -0.14 +0.12) × 10¯4 ; where the first uncertainty is statistical, the second the experimental systematic uncertainty, and the third the uncertainty due to f s/f

Measurement of the CP-violating phase phi_s in the decay Bs->J/psi phi

We present a measurement of the time-dependent CP-violating asymmetry in B_s -> J/psi phi decays, using data collected with the LHCb detector at the LHC. The decay time distribution of B_s -> J/psi phi is characterized by the decay widths Gamma_H and Gamma_L of the heavy and light mass eigenstates of the B_s-B_s-bar system and by a CP-violating phase phi_s. In a sample of about 8500 B_s -> J/psi phi events isolated from 0.37 fb^-1 of pp collisions at sqrt(s)=7 TeV we measure phi_s = 0.15 +/- 0.18 (stat) +/- 0.06 (syst) rad. We also find an average B_s decay width Gamma_s == (Gamma_L + Gamma_H)/2 = 0.657 +/- 0.009 (stat) +/- 0.008 (syst) ps^-1 and a decay width difference Delta Gamma_s == Gamma_L - Gamma_H} = 0.123 +/- 0.029 (stat) +/- 0.011 (syst) ps^-1. Our measurement is insensitive to the transformation (phi_s,DeltaGamma_s --> pi - phi_s, - Delta Gamma_s.Comment: 9 pages, 3 figure

Strong constraints on the rare decays Bs -> mu+ mu- and B0 -> mu+ mu-

A search for Bs -> mu+ mu- and B0 -> mu+ mu- decays is performed using 1.0 fb^-1 of pp collision data collected at \sqrt{s}=7 TeV with the LHCb experiment at the Large Hadron Collider. For both decays the number of observed events is consistent with expectation from background and Standard Model signal predictions. Upper limits on the branching fractions are determined to be BR(Bs -> mu+ mu-) mu+ mu-) < 1.0 (0.81) x 10^-9 at 95% (90%) confidence level.Comment: 2+6 pages; 4 figures; Accepted for publication in Physical Review Letter

First evidence of direct CP violation in charmless two-body decays of Bs mesons

Using a data sample corresponding to an integrated luminosity of 0.35 $\mathrm{fb}^{-1}$ collected by LHCb in 2011, we report the first evidence of CP violation in the decays of $B^0_s$ mesons to $K^\pm \pi^\mp$ pairs, $A_{CP}(B^0_s \rightarrow K \pi)=0.27 \pm 0.08\,\mathrm{(stat)} \pm 0.02\,\mathrm{(syst)}$, with a significance of 3.3$\sigma$. Furthermore, we report the first observation of CP violation in $B^0$ decays at a hadron collider, $A_{CP}(B^0 \rightarrow K\pi)=-0.088 \pm 0.011\,\mathrm{(stat)} \pm 0.008\,\mathrm{(syst)}$, with a significance exceeding 6$\sigma$.Comment: 8 pages, 2 figures, 2 tables; v2 with minor changes after journal revie

Measurement of charged particle multiplicities in pppp collisions at s=7{\sqrt{s} =7}TeV in the forward region

The charged particle production in proton-proton collisions is studied with the LHCb detector at a centre-of-mass energy of ${\sqrt{s} =7}$TeV in different intervals of pseudorapidity $\eta$. The charged particles are reconstructed close to the interaction region in the vertex detector, which provides high reconstruction efficiency in the $\eta$ ranges $-2.5<\eta<-2.0$ and $2.0<\eta<4.5$. The data were taken with a minimum bias trigger, only requiring one or more reconstructed tracks in the vertex detector. By selecting an event sample with at least one track with a transverse momentum greater than 1 GeV/c a hard QCD subsample is investigated. Several event generators are compared with the data; none are able to describe fully the multiplicity distributions or the charged particle density distribution as a function of $\eta$. In general, the models underestimate the charged particle production