236 research outputs found
Imbibition in Disordered Media
The physics of liquids in porous media gives rise to many interesting
phenomena, including imbibition where a viscous fluid displaces a less viscous
one. Here we discuss the theoretical and experimental progress made in recent
years in this field. The emphasis is on an interfacial description, akin to the
focus of a statistical physics approach. Coarse-grained equations of motion
have been recently presented in the literature. These contain terms that take
into account the pertinent features of imbibition: non-locality and the
quenched noise that arises from the random environment, fluctuations of the
fluid flow and capillary forces. The theoretical progress has highlighted the
presence of intrinsic length-scales that invalidate scale invariance often
assumed to be present in kinetic roughening processes such as that of a
two-phase boundary in liquid penetration. Another important fact is that the
macroscopic fluid flow, the kinetic roughening properties, and the effective
noise in the problem are all coupled. Many possible deviations from simple
scaling behaviour exist, and we outline the experimental evidence. Finally,
prospects for further work, both theoretical and experimental, are discussed.Comment: Review article, to appear in Advances in Physics, 53 pages LaTe
The four qualities of life: Ordering concepts and measures of the good life
The terms 'quality-of-life', 'wellbeing' and 'happiness' denote different meanings; sometimes they are used as an umbrella term for all of value, and the other times to denote special merits.
This paper is about the specific meanings of the terms. It proposes a classification based on two bi-partitions; between life 'chances' and life 'results', and between 'outer' and 'inner' qualities. Together these dichotomies imply four qualities of life: 1) livability of the environment, 2) life-ability of the individual, 3) external utility of life and 4) inner appreciation of life.
This fourfold matrix is applied in three ways: firstly to place related notions and alternative classifications, secondly to explore substantive meanings in various measures for quality of life and thirdly to find out whether quality-of-life can be measured comprehensively. This last question is answered in the negative. Current sum-scores make little sense. The most inclusive summary measure is still how long and happily people live
A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin–trypanothione reductase–NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis
Economic analysis including long-term risks and costs of alternative diagnostic strategies to evaluate patients with chest pain
Background: Diagnosis costs for cardiovascular disease waste a large amount of healthcare
resources. The aim of the study is to evaluate the clinical and economic outcomes of alternative
diagnostic strategies in low risk chest pain patients.
Methods: We evaluated direct and indirect downstream costs of 6 strategies: coronary
angiography (CA) after positive troponin I or T (cTn-I or cTnT) (strategy 1); after positive exercise
electrocardiography (ex-ECG) (strategy 2); after positive exercise echocardiography (ex-Echo)
(strategy 3); after positive pharmacologic stress echocardiography (PhSE) (strategy 4); after positive
myocardial exercise stress single-photon emission computed tomography with technetium Tc 99m
sestamibi (ex-SPECT-Tc) (strategy 5) and direct CA (strategy 6).
Results: The predictive accuracy in correctly identifying the patients was 83,1% for cTn-I, 87% for
cTn-T, 85,1% for ex-ECG, 93,4% for ex-Echo, 98,5% for PhSE, 89,4% for ex-SPECT-Tc and 18,7%
for CA. The cost per patient correctly identified results 2.086 for cTn-T, 803 for ex-Echo, 1.521 for ex-SPECT-Tc (29.673 for CA ($29.999 including cost of extra risk of cancer). The
average relative cost-effectiveness of cardiac imaging compared with the PhSE equal to 1 (as a cost
comparator), the relative cost of ex-Echo is 1.5×, of a ex-SPECT-Tc is 3.1×, of a ex-ECG is 3.5×,
of cTnI is ×3.8, of cTnT is ×3.9 and of a CA is 56.3×.
Conclusion: Stress echocardiography based strategies are cost-effective versus alternative
imaging strategies and the risk and cost of radiation exposure is void
Mechanism of Heparin Acceleration of Tissue Inhibitor of Metalloproteases-1 (TIMP-1) Degradation by the Human Neutrophil Elastase
Heparin has been shown to regulate human neutrophil elastase (HNE) activity. We have assessed the regulatory effect of heparin on Tissue Inhibitor of Metalloproteases-1 [TIMP-1] hydrolysis by HNE employing the recombinant form of TIMP-1 and correlated FRET-peptides comprising the TIMP-1 cleavage site. Heparin accelerates 2.5-fold TIMP-1 hydrolysis by HNE. The kinetic parameters of this reaction were monitored with the aid of a FRET-peptide substrate that mimics the TIMP-1 cleavage site in pre-steady-state conditionsby using a stopped-flow fluorescence system. The hydrolysis of the FRET-peptide substrate by HNE exhibits a pre-steady-state burst phase followed by a linear, steady-state pseudo-first-order reaction. The HNE acylation step (k2 = 21±1 s−1) was much higher than the HNE deacylation step (k3 = 0.57±0.05 s−1). The presence of heparin induces a dramatic effect in the pre-steady-state behavior of HNE. Heparin induces transient lag phase kinetics in HNE cleavage of the FRET-peptide substrate. The pre-steady-state analysis revealed that heparin affects all steps of the reaction through enhancing the ES complex concentration, increasing k1 2.4-fold and reducing k−1 3.1-fold. Heparin also promotes a 7.8-fold decrease in the k2 value, whereas the k3 value in the presence of heparin was increased 58-fold. These results clearly show that heparin binding accelerates deacylation and slows down acylation. Heparin shifts the HNE pH activity profile to the right, allowing HNE to be active at alkaline pH. Molecular docking and kinetic analysis suggest that heparin induces conformational changes in HNE structure. Here, we are showing for the first time that heparin is able to accelerate the hydrolysis of TIMP-1 by HNE. The degradation of TIMP-1is associated to important physiopathological states involving excessive activation of MMPs
Computational Fragment-Based Binding Site Identification by Ligand Competitive Saturation
Fragment-based drug discovery using NMR and x-ray crystallographic methods has proven utility but also non-trivial time, materials, and labor costs. Current computational fragment-based approaches circumvent these issues but suffer from limited representations of protein flexibility and solvation effects, leading to difficulties with rigorous ranking of fragment affinities. To overcome these limitations we describe an explicit solvent all-atom molecular dynamics methodology (SILCS: Site Identification by Ligand Competitive Saturation) that uses small aliphatic and aromatic molecules plus water molecules to map the affinity pattern of a protein for hydrophobic groups, aromatic groups, hydrogen bond donors, and hydrogen bond acceptors. By simultaneously incorporating ligands representative of all these functionalities, the method is an in silico free energy-based competition assay that generates three-dimensional probability maps of fragment binding (FragMaps) indicating favorable fragment∶protein interactions. Applied to the two-fold symmetric oncoprotein BCL-6, the SILCS method yields two-fold symmetric FragMaps that recapitulate the crystallographic binding modes of the SMRT and BCOR peptides. These FragMaps account both for important sequence and structure differences in the C-terminal halves of the two peptides and also the high mobility of the BCL-6 His116 sidechain in the peptide-binding groove. Such SILCS FragMaps can be used to qualitatively inform the design of small-molecule inhibitors or as scoring grids for high-throughput in silico docking that incorporate both an atomic-level description of solvation and protein flexibility
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