Enzymatic Characterization of ER Stress-Dependent Kinase, PERK, and Development of a High-Throughput Assay for Identification of PERK Inhibitors

PERK is serine/threonine kinase localized to the endoplasmic reticulum (ER) membrane. PERK is activated and contributes to cell survival in response to a variety of physiological stresses that affect protein quality control in the ER, such as hypoxia, glucose depravation, increased lipid biosynthesis, and increased protein translation. Pro-survival functions of PERK are triggered by such stresses, suggesting that development of small-molecule inhibitors of PERK may be efficacious in a variety of disease scenarios. Hence, we have conducted a detailed enzymatic characterization of the PERK kinase to develop a high-throughput-screening assay (HTS) that will permit the identification of small-molecule PERK inhibitors. In addition to establishing the Km of PERK for both its primary substrate, eIF2?, and for adenosine triphosphate, further mechanistic studies revealed that PERK targets its substrate via either a random/steady-state ordered mechanism. For HTS, we developed a time-resolved fluorescence resonance energy transfer–based assay that yielded a robust Z? factor and percent coefficient of variation value, enabling the successful screening of 79,552 compounds. This approach yielded one compound that exhibited good in vitro and cellular activity. These results demonstrate the validity of this screen and represent starting points for drug discovery efforts

Rescattering and chiral dynamics in B\to \rho\pi decay

We examine the role of B^0(\bar B^0) \to \sigma \pi^0 \to \pi^+\pi^- \pi^0 decay in the Dalitz plot analysis of B^0 (\bar B^0) \to \rho\pi \to \pi^+\pi^-\pi^0 decays, employed to extract the CKM parameter \alpha. The \sigma \pi channel is significant because it can break the relationship between the penguin contributions in B\to\rho^0\pi^0, B\to\rho^+\pi^-, and B\to\rho^-\pi^+ decays consequent to an assumption of isospin symmetry. Its presence thus mimics the effect of isospin violation. The \sigma\pi^0 state is of definite CP, however; we demonstrate that the B\to\rho\pi analysis can be generalized to include this channel without difficulty. The \sigma or f_0(400-1200) ``meson'' is a broad I=J=0 enhancement driven by strong \pi\pi rescattering; a suitable scalar form factor is constrained by the chiral dynamics of low-energy hadron-hadron interactions - it is rather different from the relativistic Breit-Wigner form adopted in earlier B\to\sigma\pi and D\to\sigma\pi analyses. We show that the use of this scalar form factor leads to an improved theoretical understanding of the measured ratio Br(\bar B^0 \to \rho^\mp \pi^\pm) / Br(B^-\to \rho^0 \pi^-).Comment: 26 pages, 8 figs, published version. typos fixed, minor change

CP asymmetries in the supersymmetric trilepton signal at the LHC

In the CP-violating Minimal Supersymmetric Standard Model, we study the production of a neutralino-chargino pair at the LHC. For their decays into three leptons, we analyze CP asymmetries which are sensitive to the CP phases of the neutralino and chargino sector. We present analytical formulas for the entire production and decay process, and identify the CP-violating contributions in the spin correlation terms. This allows us to define the optimal CP asymmetries. We present a detailed numerical analysis of the cross sections, branching ratios, and the CP observables. For light neutralinos, charginos, and squarks, the asymmetries can reach several 10%. We estimate the discovery potential for the LHC to observe CP violation in the trilepton channel.Comment: 39 pages, 8 figures, version to appear in EPJC, discussion(s) added, typo in (D.79), (D.118) corrected, new Fig. 7; The European Physical Journal C, Volume 72, Issue 3, 201

CP Violation in radiative Z Decays

We propose to test the CP symmetry in the reactions Z -> mu+ mu- gamma and Z -> tau+ tau- gamma. The experimental analysis of angular correlations allows to determine a set of effective couplings: the electric and weak dipole moments of the muon and the tau lepton, and in particular chirality conserving 4-particle couplings, all of which can be induced by CP--violation in renormalizable theories of electroweak interactions beyond the Standard Model. We update an indirect bound on the weak dipole moment of the muon.Comment: 19 pages, Latex, 4 Figures in PostScript forma

Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis

Choline metabolism is important for very low-density lipoprotein secretion, making this nutritional pathway an important contributor to hepatic lipid balance. The purpose of this study was to assess whether the cumulative effects of multiple single nucleotide polymorphisms (SNPs) across genes of choline/ 1-carbon metabolism and functionally related pathways increase susceptibility to developing hepatic steatosis. In biopsy-characterized cases of nonalcoholic fatty liver disease and controls, we assessed 260 SNPs across 21 genes in choline/1-carbon metabolism. When SNPs were examined individually, using logistic regression, we only identified a single SNP (PNPLA3 rs738409) that was significantly associated with severity of hepatic steatosis after adjusting for confounders and multiple comparisons (P=0.02). However, when groupings of SNPs in similar metabolic pathways were defined using unsupervised hierarchical clustering, we identified groups of subjects with shared SNP signatures that were significantly correlated with steatosis burden (P=0.0002). The lowest and highest steatosis clusters could also be differentiated by ethnicity. However, unique SNP patterns defined steatosis burden irrespective of ethnicity. Our results suggest that analysis of SNP patterns in genes of choline/1-carbon metabolism may be useful for prediction of severity of steatosis in specific subsets of people, and the metabolic inefficiencies caused by these SNPs should be examined further

Evidence of Color Coherence Effects in W+jets Events from ppbar Collisions at sqrt(s) = 1.8 TeV

We report the results of a study of color coherence effects in ppbar collisions based on data collected by the D0 detector during the 1994-1995 run of the Fermilab Tevatron Collider, at a center of mass energy sqrt(s) = 1.8 TeV. Initial-to-final state color interference effects are studied by examining particle distribution patterns in events with a W boson and at least one jet. The data are compared to Monte Carlo simulations with different color coherence implementations and to an analytic modified-leading-logarithm perturbative calculation based on the local parton-hadron duality hypothesis.Comment: 13 pages, 6 figures. Submitted to Physics Letters