The case for low-level BACE1 inhibition for the prevention of Alzheimer disease

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform ‘go–no-go’ decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry

Impact damage characteristics of carbon fibre metal laminates : experiments and simulation

In this work, the impact response of carbon fibre metal laminates (FMLs) was experimentally and numerically studied with an improved design of the fibre composite lay-up for optimal mechanical properties and damage resistance. Two different stacking sequences (Carall 3–3/2–0.5 and Carall 5–3/2–0.5) were designed and characterised. Damage at relatively low energy impact energies (≤30 J) was investigated using Ultrasonic C-scanning and X–ray Computed Tomography (X-RCT). A 3D finite element model was developed to simulate the impact induced damage in both metal and composite layers using Abaqus/Explicit. Cohesive zone elements were introduced to capture delamination occurring between carbon fibre/epoxy plies and debonding at the interfaces between aluminium and the composite layers. Carall 5–3/2–0.5 was found to absorb more energy elastically, which indicates better resistance to damage. A good agreement is obtained between the numerically predicted results and experimental measurements in terms of force and absorbed energy during impact where the damage modes such as delamination was well simulated when compared to non-destructive techniques (NDT)

Potential Use of a Serpin from Arabidopsis for Pest Control

Although genetically modified (GM) plants expressing toxins from Bacillus thuringiensis (Bt) protect agricultural crops against lepidopteran and coleopteran pests, field-evolved resistance to Bt toxins has been reported for populations of several lepidopteran species. Moreover, some important agricultural pests, like phloem-feeding insects, are not susceptible to Bt crops. Complementary pest control strategies are therefore necessary to assure that the benefits provided by those insect-resistant transgenic plants are not compromised and to target those pests that are not susceptible. Experimental GM plants producing plant protease inhibitors have been shown to confer resistance against a wide range of agricultural pests. In this study we assessed the potential of AtSerpin1, a serpin from Arabidopsis thaliana (L). Heynh., for pest control. In vitro assays were conducted with a wide range of pests that rely mainly on either serine or cysteine proteases for digestion and also with three non-target organisms occurring in agricultural crops. AtSerpin1 inhibited proteases from all pest and non-target species assayed. Subsequently, the cotton leafworm Spodoptera littoralis Boisduval and the pea aphid Acyrthosiphon pisum (Harris) were fed on artificial diets containing AtSerpin1, and S. littoralis was also fed on transgenic Arabidopsis plants overproducing AtSerpin1. AtSerpin1 supplied in the artificial diet or by transgenic plants reduced the growth of S. littoralis larvae by 65% and 38%, respectively, relative to controls. Nymphs of A. pisum exposed to diets containing AtSerpin1 suffered high mortality levels (LC50 = 637 µg ml−1). The results indicate that AtSerpin1 is a good candidate for exploitation in pest control

Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron

We study the underlying event in proton-antiproton collisions by examining the behavior of charged particles (transverse momentum pT > 0.5 GeV/c, pseudorapidity |\eta| < 1) produced in association with large transverse momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan production) or the leading jet (in high-pT jet production) in each event to define three regions of \eta-\phi space; toward, away, and transverse, where \phi is the azimuthal scattering angle. For Drell-Yan production (excluding the leptons) both the toward and transverse regions are very sensitive to the underlying event. In high-pT jet production the transverse region is very sensitive to the underlying event and is separated into a MAX and MIN transverse region, which helps separate the hard component (initial and final-state radiation) from the beam-beam remnant and multiple parton interaction components of the scattering. The data are corrected to the particle level to remove detector effects and are then compared with several QCD Monte-Carlo models. The goal of this analysis is to provide data that can be used to test and improve the QCD Monte-Carlo models of the underlying event that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.

Measurement of the Lambda_b Lifetime in Lambda_b --> J/psi Lambda0 in p-pbar Collisions at sqrt(s)=1.96 TeV

We report a measurement of the Lambda_b lifetime in the exclusive decay Lambda_b --> J/psi Lambda0 in p-pbar collisions at sqrt(s) = 1.96 TeV using an integrated luminosity of 1.0 fb^{-1} of data collected by the CDF II detector at the Fermilab Tevatron. Using fully reconstructed decays, we measure tau(Lambda_b) = 1.593 ^{+0.083}_{-0.078} (stat.) +- 0.033 (syst.) ps. This is the single most precise measurement of tau(Lambda_b) and is 3.2 sigma higher than the current world average.Comment: 7 Pages, 2 Figures, 1 Table. Submitted to Phys. Rev. Let

Measurement of Lifetime and Decay-Width Difference in B0s -> J/psi phi Decays

We measure the mean lifetime, tau=2/(Gamma_L+Gamma_H), and the width difference, DeltaGamma=Gamma_L-Gamma_H, of the light and heavy mass eigenstates of the B0s meson, B0sL and B0sH, in B0s -> J/psi phi decays using 1.7 fb^-1 of data collected with the CDF II detector at the Fermilab Tevatron ppbar collider. Assuming CP conservation, a good approximation for the B0s system in the Standard Model, we obtain DeltaGamma = 0.076^+0.059_-0.063 (stat.) +- 0.006 (syst.) ps^-1 and tau = 1.52 +- 0.04 (stat.) +- 0.02 (syst.) ps, the most precise measurements to date. Our constraints on the weak phase and DeltaGamma are consistent with CP conservation. Dedicated to the memory of our dear friend and colleague, Michael P. Schmid

Measurement of the W+W−W^+W^- Production Cross Section and Search for Anomalous WWγWW\gamma and WWZWWZ Couplings in ppˉp \bar p Collisions at s=1.96\sqrt{s} = 1.96 TeV

This Letter describes the current most precise measurement of the $W$ boson pair production cross section and most sensitive test of anomalous $WW\gamma$ and $WWZ$ couplings in $p \bar p$ collisions at a center-of-mass energy of 1.96 TeV. The $WW$ candidates are reconstructed from decays containing two charged leptons and two neutrinos, where the charged leptons are either electrons or muons. Using data collected by the CDF II detector from 3.6 fb$^{-1}$ of integrated luminosity, a total of 654 candidate events are observed with an expected background contribution of $320 \pm 47$ events. The measured total cross section is $\sigma (p \bar p \to W^+ W^- + X) = 12.1 \pm 0.9 \textrm{(stat)} ^{+1.6}_{-1.4} \textrm{(syst)}$ pb, which is in good agreement with the standard model prediction. The same data sample is used to place constraints on anomalous $WW\gamma$ and $WWZ$ couplings.Comment: submitted to Phys. Rev. Let

Search for Pair Production of Scalar Top Quarks Decaying to a tau Lepton and a b Quark in ppbar Collisions at sqrt{s}=1.96 TeV

We search for pair production of supersymmetric top quarks (~t_1), followed by R-parity violating decay ~t_1 -> tau b with a branching ratio beta, using 322 pb^-1 of ppbar collisions at sqrt{s}=1.96 TeV collected by the CDF II detector at Fermilab. Two candidate events pass our final selection criteria, consistent with the standard model expectation. We set upper limits on the cross section sigma(~t_1 ~tbar_1)*beta^2 as a function of the stop mass m(~t_1). Assuming beta=1, we set a 95% confidence level limit m(~t_1)>153 GeV/c^2. The limits are also applicable to the case of a third generation scalar leptoquark (LQ_3) decaying LQ_3 -> tau b.Comment: 7 pages, 2 eps figure

Observation of Bs-Bsbar Oscillations

We report the observation of Bs-Bsbar oscillations from a time-dependent measurement of the Bs-Bsbar oscillation frequency Delta ms. Using a data sample of 1 fb^-1 of p-pbar collisions at sqrt{s}=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron, we find signals of 5600 fully reconstructed hadronic Bs decays, 3100 partially reconstructed hadronic Bs decays, and 61500 partially reconstructed semileptonic Bs decays. We measure the probability as a function of proper decay time that the Bs decays with the same, or opposite, flavor as the flavor at production, and we find a signal for Bs-Bsbar oscillations. The probability that random fluctuations could produce a comparable signal is 8 X 10^-8, which exceeds 5 sigma significance. We measure Delta ms = 17.77 +- 0.10 (stat) +- 0.07 (syst) ps^-1 and extract |Vtd/Vts| = 0.2060 +- 0.0007 (exp) + 0.0081 - 0.0060 (theor).Comment: 9 pages, 5 figures, submitted to Physical Review Letter