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101.
102.
Protein kinases control virtually every aspect of normal and pathological cell physiology and are considered ideal targets for drug discovery. Most kinase inhibitors target the ATP binding site and interact with residue of a hinge loop connecting the small and large lobes of the kinase scaffold. Resistance to kinase inhibitors emerges during clinical treatment or as a result of in vitro selection approaches. Mutations conferring resistance to ATP site inhibitors often affect residues that line the ATP binding site and therefore contribute to selective inhibitor binding. Here, we show that mutations at two specific positions in the hinge loop, distinct from the previously characterized "gatekeeper," have general adverse effects on inhibitor sensitivity in six distantly related kinases, usually without consequences on kinase activity. Our results uncover a unifying mechanism of inhibitor resistance of protein kinases that might have widespread significance for drug target validation and clinical practice. 相似文献
103.
M. Fabrizio G. Matarazzo M. Pecoraro 《Zeitschrift für Angewandte Mathematik und Physik (ZAMP)》2011,62(6):1013-1026
In this paper, by an extension of the Ginzburg–Landau theory, we propose a mathematical model describing hard magnets within which we are able to explore the para–ferromagnetic transition and by using the Landau–Lifshitz–Gilbert equation, to study the 3D evolution of magnetic field. Finally, the hysteresis loops are obtained and represented by numerical implementations. 相似文献
104.
105.
Badaloni E Barbarino M Cabri W D'Acquarica I Forte M Gasparrini F Giorgi F Pierini M Simone P Ursini O Villani C 《Journal of chromatography. A》2011,1218(25):3862-3875
New monolithic HPLC columns were prepared by γ-radiation-triggered polymerization of hexyl methacrylate and ethylene glycol dimethacrylate monomers in the presence of porogenic solvents. Polymerization was carried out directly within capillary (250-200 μm I.D.) and nano (100-75 μm I.D.) fused-silica tubes yielding highly efficient columns for cap(nano)-LC applications. The columns were applied in the complete separation of core (H2A, H2B, H3, and H4) and linker (H1) histones under gradient elution with UV and/or electrospray ionization (ESI) ion trap mass spectrometry (MS) detections. Large selectivity towards H1, H2A-1, H2A-2, H2B, H3-1, H3-2 and H4 histones and complete separation were obtained within 8 min time windows, using fast gradients and very high linear flow velocities, up to 11 mm/s for high throughput applications. The method developed was the basis of a simple and efficient protocol for the evaluation of post-translational modifications (PTMs) of histones from NCI-H460 human non-small-cell lung cancer (NSCLC) and HCT-116 human colorectal carcinoma cells. The study was extended to monitoring the level of histone acetylation after inhibition of Histone DeACetylase (HDAC) enzymes with suberoylanilide hydroxamic acid (SAHA), the first HDAC inhibitor approved by the FDA for cancer therapy. Attractive features of our cap(nano)-LC/MS approach are the short analysis time, the minute amount of sample required to complete the whole procedure and the stability of the polymethacrylate-based columns. A lab-made software package ClustMass was ad hoc developed and used to elaborate deconvoluted mass spectral data (aligning, averaging, clustering) and calculate the potency of HDAC inhibitors, expressed through a Relative half maximal Inhibitory Concentration parameter, namely R_IC(50) and an averaged acetylation degree. 相似文献
106.
Acid-base interaction between transition-metal hydrides: dihydrogen bonding and dihydrogen evolution
107.
A system with piecewise linear restoring forces, typical of damaged beams with a breathing crack, exhibits bifurcations characterized
by the onset of superabundant modes in internal resonance with a significantly different shape than that of modes on a fundamental
branch. A 2-DOF frame with piecewise linear stiffness is analyzed by means of an experimental investigation; the frame is
forced by an harmonic base excitation and the operative modal shapes as well as the response amplitude are directly measured;
the results are compared with numerical outcomes for different damping values. This study shows that the shapes and the frequencies
of certain nonlinear normal modes (NNMs) of the related autonomous system strongly affect the forced response, in both the
numerical and the experimental environments. Therefore, it is possible to match the NNM with the forced response of the system,
leading to the prospect of identifying the severity and position of the damage from experimental tests. 相似文献
108.
Fabrizio Caselli 《Israel Journal of Mathematics》2011,185(1):155-187
109.
110.
F. Rodante G. Marrosu G. Catalani 《Journal of Thermal Analysis and Calorimetry》1992,38(12):2669-2682
The thermal analysis of some pesticides using simultaneous TG-DSC measurements and kinetic calculations by the dynamic TG technique have been carried out.With this technique it was attempted to group compounds with similar structures according to the shape and number of peaks of their thermoanalytical curves and to characterize their features by means of thermodynamic and kinetic quantities.Small variations in the structure of the components of a class make larger variations in the thermodynamic and kinetic values being in close agreement with the observed differences in their biological behaviour.
Zusammenfassung Mittels simultanen TG-DSC-Messungen und kinetischen Berechnungen bei der DTG-Technik wurde eine thermische Analyse einiger Pestizide durchgeführt.Mit dieser Methode wurde versucht, Verbindungen mit ähnlichen Strukturen anhand der Form und Anzahl von Peaks ihrer thermoanalytischen Kurven zu gruppieren und ihre Eigenschaften mittels thermodynamischen und kinetischen Mengen zu charakterisieren.Geringe Änderungen in der Struktur der Komponenten einer Klasse verursachen größere Veränderungen der thermodynamischen und kinetischen Größen, was in enger Übereinstimmung mit den beobachteten Unterschieden ihrer biologischen Aktivität steht.相似文献