Improved Formalism for Precision Higgs Coupling Fits

Future e+e- colliders give the promise of model-independent determinations of the couplings of the Higgs boson. In this paper, we present an improved formalism for extracting Higgs boson couplings from e+e- data, based on the Effective Field Theory description of corrections to the Standard Model. We apply this formalism to give projections of Higgs coupling accuracies for stages of the International Linear Collider and for other proposed e+e- colliders.Comment: 34 pages, 4 figures; v4: clarifications and new references added; v5, additional references adde

A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model.

We describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer's disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity. We were able to resolve the enantiomers of A03 and show using in vitro models that the L-enantiomer was more potent than the corresponding D-enantiomer in increasing SirT1 levels. ApoE4 expression has been shown to decrease the level of the NAD-dependent deacetylase and major longevity determinant SirT1 in brain tissue and serum of AD patients as compared to normal controls. A deficiency in SirT1 level has been recently implicated in increased tau acetylation, a dominant post-translational modification and key pathological event in AD and tauopathies. Therefore, as a novel approach to therapeutic development for AD, we targeted identification of compounds that enhance and normalize brain SirT1 levels

Detection of anomalies in software architecture with connectors

AbstractThis paper describes an approach to detecting anomalies in a software architectural style that is structured with components and connectors between the components. Each component is designed with tasks (concurrent or active objects), connectors between tasks, and passive objects accessed by tasks. Anomalies in the software architecture are detected twofold by each Component Monitor, which supervises objects in a component, and by a System Monitor, which monitors message communications between components. The monitors encapsulate the specifications of objects being monitored, which are represented using statecharts. The execution of statecharts in the monitors depends on notification messages from connectors between tasks, passive objects accessed by tasks in a component, and connectors between components

Graphene Oxidation: Thickness Dependent Etching and Strong Chemical Doping

Patterned graphene shows substantial potential for applications in future molecular-scale integrated electronics. Environmental effects are a critical issue in a single layer material where every atom is on the surface. Especially intriguing is the variety of rich chemical interactions shown by molecular oxygen with aromatic molecules. We find that O2 etching kinetics vary strongly with the number of graphene layers in the sample. Three-layer-thick samples show etching similar to bulk natural graphite. Single-layer graphene reacts faster and shows random etch pits in contrast to natural graphite where nucleation occurs at point defects. In addition, basal plane oxygen species strongly hole dope graphene, with a Fermi level shift of ~0.5 eV. These oxygen species partially desorb in an Ar gas flow, or under irradiation by far UV light, and readsorb again in an O2 atmosphere at room temperature. This strongly doped graphene is very different than graphene oxide made by mineral acid attack.Comment: 15 pages, 5 figure

Design of Transgenic S. cerevisiae for Enzymatic Pretreatment

Biofuels, combustible fuel produced from fermentation of agricultural biomass by microorganisms, represent one of the best possible paths forward for sustainable energy production. However, inefficiencies in biofuel production create barriers that stand in the way of their widespread adoption. One such barrier is the breakdown of lignin, a biopolymer that exists on the edge of plant cell walls which protects the sugars that are used in fermentation. Currently, lignin is broken down in energy-intensive thermal pretreatment processes. A viable alternative is the expression of lignin-degrading enzymes by synthetic microorganisms that work at standard temperatures, eliminating the need for the high-energy input of thermal pretreatment. Four lignin-degrading enzymes were selected from termites (R. flavipes) and white rot fungus(C. fioriniae PJ7) and two helper enzymes that assist in lignin degradation were selected and then optimized for expression in yeast. The genetic devices amplified were assembled using standard DNA assembly methods. Future transformation into yeast (S. cerevisiae) cells and testing of lignin-breakdown effectiveness may open up an alternative path for thermal pretreatment of biomass

Cooperative Control for Target Tracking with Onboard Sensing

Abstract We consider the cooperative control of a team of robots to estimate the position of a moving target using onboard sensing. In particular, we do not as-sume that the robot positions are known, but estimate their positions using relative onboard sensing. Our probabilistic localization and control method takes into ac-count the motion and sensing capabilities of the individual robots to minimize the expected future uncertainty of the target position. It reasons about multiple possi-ble sensing topologies and incorporates an efficient topology switching technique to generate locally optimal controls in polynomial time complexity. Simulations show the performance of our approach and prove its flexibility to find suitable sensing topologies depending on the limited sensing capabilities of the robots and the movements of the target. Furthermore, we demonstrate the applicability of our method in various experiments with single and multiple quadrotor robots tracking a ground vehicle in an indoor environment

The rigid amphipathic fusion Inhibitor dUY11 acts through photosensitization of viruses

Copyright © 2014, American Society for Microbiology. All Rights Reserved.Supplemental material for this article may be found at http://dx.doi.org/10.1128 /JVI.02907-13.Rigid amphipathic fusion inhibitors (RAFIs) are lipophilic inverted-cone-shaped molecules thought to antagonize the membrane curvature transitions that occur during virus-cell fusion and are broad-spectrum antivirals against enveloped viruses (Broad-SAVE). Here, we show that RAFIs act like membrane-binding photosensitizers: their antiviral effect is dependent on light and the generation of singlet oxygen (1O2), similar to the mechanistic paradigm established for LJ001, a chemically unrelated class of Broad-SAVE. Photosensitization of viral membranes is a common mechanism that underlies these Broad-SAVE.This work was supported by NIH grants U01 AI070495, U01 AI082100, R01 AI069317, and U54 AI065359 (PSWRCE) (to B.L.) and by Fundação para a Ciência e a Tecnologia-Ministério da Educação e Ciência (Portugal) project DELIN-HIVERA/0002/2013 and fellowship SFRH/BPD/72037/2010 (to N.C.S. and A.H., respectively

The cap-snatching SFTSV endonuclease domain is an antiviral target

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with 12%-30% case mortality rates and is related to the Heartland virus (HRTV) identified in the United States. Together, SFTSV and HRTV are emerging segmented, negative-sense RNA viral (sNSV) pathogens with potential global health impact. Here, we characterize the amino-terminal cap-snatching endonuclease domain of SFTSV polymerase (L) and solve a 2.4-Å X-ray crystal structure. While the overall structure is similar to those of other cap-snatching sNSV endonucleases, differences near the C terminus of the SFTSV endonuclease suggest divergence in regulation. Influenza virus endonuclease inhibitors, including the US Food and Drug Administration (FDA) approved Baloxavir (BXA), inhibit the endonuclease activity in in vitro enzymatic assays and in cell-based studies. BXA displays potent activity with a half maximal inhibitory concentration (I

Heterochromatin is refractory to γ-H2AX modification in yeast and mammals

Double-strand break (DSB) damage in yeast and mammalian cells induces the rapid ATM (ataxia telangiectasia mutated)/ATR (ataxia telangiectasia and Rad3 related)-dependent phosphorylation of histone H2AX (γ-H2AX). In budding yeast, a single endonuclease-induced DSB triggers γ-H2AX modification of 50 kb on either side of the DSB. The extent of γ-H2AX spreading does not depend on the chromosomal sequences. DNA resection after DSB formation causes the slow, progressive loss of γ-H2AX from single-stranded DNA and, after several hours, the Mec1 (ATR)-dependent spreading of γ-H2AX to more distant regions. Heterochromatic sequences are only weakly modified upon insertion of a 3-kb silent HMR locus into a γ-H2AX–covered region. The presence of heterochromatin does not stop the phosphorylation of chromatin more distant from the DSB. In mouse embryo fibroblasts, γ-H2AX distribution shows that γ-H2AX foci increase in size as chromatin becomes more accessible. In yeast, we see a high level of constitutive γ-H2AX in telomere regions in the absence of any exogenous DNA damage, suggesting that yeast chromosome ends are transiently detected as DSBs