1,516 research outputs found
Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms
BACKGROUND AND PURPOSE Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drugdrug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression. KEY RESULTS Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. CONCLUSIONS AND IMPLICATIONS Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR-dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo, whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme-inducing metabolite. For better understanding of pharmacokinetic drugdrug interaction possibilities, the inducing properties of artemisinin metabolites should be considered.German Federal Ministry of Education and Research (BMBF) HepatosSys network [0313081B, 0313080F, 0313080I]; Deutsche Forschungsgemeinschaft (Germany) [KE 1629/1-1]; Robert Bosch Foundation, Stuttgart, Germanyinfo:eu-repo/semantics/publishedVersio
Inner Hair Cell Loss Disrupts Hearing and Cochlear Function Leading to Sensory Deprivation and Enhanced Central Auditory Gain
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A Fiscal Stimulus and Jobless Recovery
We analyze the effects of a government-spending expansion in a dynamic stochastic general equilibrium model with Mortensen–Pissarides labor-market frictions, deep habits in private and public consumption, investment adjustment costs, a constant elasticity of substitution (CES) production function, and adjustments in employment at both intensive and extensive margins. The combination of deep habits and CES technology is crucial. The presence of deep habits magnifies the responses of macroeconomic variables to a fiscal stimulus, while an elasticity of substitution between capital and labor in the range of available estimates allows the model to produce a scenario compatible with the observed jobless recovery
Green's function formalism for spin transport in metal-insulator-metal heterostructures
Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model
BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV
Virtual Compton Scattering and Neutral Pion Electroproduction in the Resonance Region up to the Deep Inelastic Region at Backward Angles
We have made the first measurements of the virtual Compton scattering (VCS)
process via the H exclusive reaction in the nucleon resonance
region, at backward angles. Results are presented for the -dependence at
fixed GeV, and for the -dependence at fixed near 1.5 GeV.
The VCS data show resonant structures in the first and second resonance
regions. The observed -dependence is smooth. The measured ratio of
H to H cross sections emphasizes the different
sensitivity of these two reactions to the various nucleon resonances. Finally,
when compared to Real Compton Scattering (RCS) at high energy and large angles,
our VCS data at the highest (1.8-1.9 GeV) show a striking -
independence, which may suggest a transition to a perturbative scattering
mechanism at the quark level.Comment: 20 pages, 8 figures. To appear in Phys.Rev.
Virtual Compton Scattering and the Generalized Polarizabilities of the Proton at Q^2=0.92 and 1.76 GeV^2
Virtual Compton Scattering (VCS) on the proton has been studied at Jefferson
Lab using the exclusive photon electroproduction reaction (e p --> e p gamma).
This paper gives a detailed account of the analysis which has led to the
determination of the structure functions P_LL-P_TT/epsilon and P_LT, and the
electric and magnetic generalized polarizabilities (GPs) alpha_E(Q^2) and
beta_M(Q^2) at values of the four-momentum transfer squared Q^2= 0.92 and 1.76
GeV^2. These data, together with the results of VCS experiments at lower
momenta, help building a coherent picture of the electric and magnetic GPs of
the proton over the full measured Q^2-range, and point to their non-trivial
behavior.Comment: version 2: modified according to PRC Editor's and Referee's
recommendations. Archival paper for the E93-050 experiment at JLab Hall A. 28
pages, 23 figures, 5 cross-section tables. To be submitted to Phys.Rev.
Backward electroproduction of pi0 mesons on protons in the region of nucleon resonances at four momentum transfer squared Q**2 = 1.0 GeV**2
Exclusive electroproduction of pi0 mesons on protons in the backward
hemisphere has been studied at Q**2 = 1.0 GeV**2 by detecting protons in the
forward direction in coincidence with scattered electrons from the 4 GeV
electron beam in Jefferson Lab's Hall A. The data span the range of the total
(gamma* p) center-of-mass energy W from the pion production threshold to W =
2.0 GeV. The differential cross sections sigma_T+epsilon*sigma_L, sigma_TL, and
sigma_TT were separated from the azimuthal distribution and are presented
together with the MAID and SAID parametrizations.Comment: 17 pages, 11 figures, information can be found at
http://hallaweb.jlab.org/experiment/E93-050/vcs.html updated content about
SAID analysis updated MAID results following new reference nucl-th/0310041
updated figure
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Putting susceptibility on the map to improve conservation planning, an example with terrestrial mammals
Aim
To propose a general approach to spatially synthesize known predictors of vulnerability at the species level in order to identify areas directly associated with specific conservation problems. Under this problem-detection framework, the coincidence or divergence of main strengths and weaknesses can be used to propose tailor-made conservation strategies. This approach is illustrated for terrestrial mammal species evaluating two of their main components of vulnerability: life-history traits and land use pressure.
Location
Global.
Methods
We determine, at the species level, the relationships between extinction risk and two well-known predictors of vulnerability: life-history traits (intrinsic) and land use (extrinsic). Transferring these findings into the spatial domain, we identify the areas of the world where one of these two facets is predominant and those areas where both coincide.
Results
The proposed approach allows us to recognize four types of areas: 1) double-susceptibility areas: where both the characteristics of the species and the existing human activities pose a threat, therefore the simultaneous management of both species/habitats and human activities are needed; 2) intrinsic-susceptibility areas: where species are naturally fragile and human presence is scarce, thus species-specific management plans would be particularly efficient; 3) extrinsic-susceptibility areas: where human pressure is high but species are not intrinsically vulnerable; which requires special attention to human activities; and 4) low-susceptibility areas: where there are not remarkable threats for existing terrestrial mammals, which additionally are not particularly fragile.
Main conclusions
Our approach can spatially synthesize known predictors of vulnerability identifying areas where different factors predispose species to become extinct. This method builds on conservation planning approaches by targeting actions based on known strengths and weaknesses of a given area, and offering a new implementation of comparative studies of extinction risk. This approach may be applied to different species and to particular regions, focusing on different drivers, and complemented by incorporating social and economic trade-offs
Induced pseudoscalar coupling of the proton weak interaction
The induced pseudoscalar coupling is the least well known of the weak
coupling constants of the proton's charged--current interaction. Its size is
dictated by chiral symmetry arguments, and its measurement represents an
important test of quantum chromodynamics at low energies. During the past
decade a large body of new data relevant to the coupling has been
accumulated. This data includes measurements of radiative and non radiative
muon capture on targets ranging from hydrogen and few--nucleon systems to
complex nuclei. Herein the authors review the theoretical underpinnings of
, the experimental studies of , and the procedures and uncertainties
in extracting the coupling from data. Current puzzles are highlighted and
future opportunities are discussed.Comment: 58 pages, Latex, Revtex4, prepared for Reviews of Modern Physic
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