Structural Insights into the Inhibition of Cytosolic 5′-Nucleotidase II (cN-II) by Ribonucleoside 5′-Monophosphate Analogues

Cytosolic 5′-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5′-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5′-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues

Force plate monitoring of human hemodynamics

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Noninvasive recording of movements caused by the heartbeat and the blood circulation is known as ballistocardiography. Several studies have shown the capability of a force plate to detect cardiac activity in the human body. The aim of this paper is to present a new method based on differential geometry of curves to handle multivariate time series obtained by ballistocardiographic force plate measurements. Results: We show that the recoils of the body caused by cardiac motion and blood circulation provide a noninvasive method of displaying the motions of the heart muscle and the propagation of the pulse wave along the aorta and its branches. The results are compared with the data obtained invasively during a cardiac catheterization. We show that the described noninvasive method is able to determine the moment of a particular heart movement or the time when the pulse wave reaches certain morphological structure. Conclusions: Monitoring of heart movements and pulse wave propagation may be used e.g. to estimate the aortic pulse wave velocity, which is widely accepted as an index of aortic stiffness wit

Proton spin-lattice relaxation study of the neutral-to-ionic transition in TTF-chloranil

The neutral to ionic transition of tetrathiafulvalene-p-chloranil is studied by nuclear magnetic resonance. Whereas the second moment of the 1H resonance line is not appreciably sensitive to this phase transition, because no large amplitude motions are concerned, the proton spin-lattice relaxation time T1 presents an obvious discontinuity at TN-I. This behaviour is discussed in terms of the created paramagnetic species related to the dimerization in the ionic phase.Nous présentons une étude par R.M.N. de la transition neutre-ionique du tétrathiafulvalène-p-chloranile. Alors que le second moment de la raie de résonance du proton n'est pas sensiblement affecté par cette transition de phase ne concernant pas de mouvement de grandes amplitudes, le temps de relaxation spin-réseau présente une nette discontinuité à TN-I. Ce comportement est discuté en considérant les centres paramagnétiques créés en relation avec la dimérisation de la phase ionique