GPCRmd uncovers the dynamics of the 3D-GPCRome Rodríguez-Espigares, Ismael; Torrens-Fontanals, Mariona; Tiemann, Johanna K S ...
Nature methods,
08/2020, Letnik:
17, Številka:
8
Journal Article
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G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) ...molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. Molecular dynamics (MD) simulations have become a widely established technique for exploring the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations require efficient storage resources and specialized software. Here we present GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyze and share GPCR MD data. GPCRmd originates from a community-driven effort to create an open, interactive and standardized database of GPCR MD simulations.
A simple, fast and upscalable method is described to produce graphene/alumina (G/Al2O3) composites by spark plasma sintering (SPS) with a significant improvement on both mechanical and electrical ...properties of monolithic Al2O3. Graphene oxide (GO) was mixed with Al2O3 using a colloidal method obtaining an excellent dispersion of GO in the alumina matrix. The material was consolidated by SPS that allowed, in one-step, the in situ reduction of the GO during the sintering process. A detailed Raman analysis was found to be very useful to study the orientation of the graphene in the composite and to evaluate and optimise its thermal reduction. Graphene platelets acted as elastic bridges avoiding crack propagation and providing this material with a crack bridging reinforcement mechanism. A very low graphene loading (0.22wt%) led to a 50% improvement on the mechanical properties of the alumina and to an increase of the electrical conductivity up to eight orders of magnitude.
Human exposure to nanomaterials and nanoparticles is increasing rapidly, but their effects on human health are still largely unknown. Epigenetic modifications are attracting ever more interest as ...possible underlying molecular mechanisms of gene-environment interactions, highlighting them as potential molecular targets following exposure to nanomaterials and nanoparticles. Interestingly, recent research has identified changes in DNA methylation, histone post-translational modifications, and noncoding RNAs in mammalian cells exposed to nanomaterials and nanoparticles. However, the challenge for the future will be to determine the molecular pathways driving these epigenetic alterations, the possible functional consequences, and the potential effects on health.
Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. ...However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 UCM-1336, IC50 = 2 μM, which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.
This paper presents a study on graphene-reinforced Al2O3-SiCw ceramic composites and the relationship between graphene oxide (GO) loading and the resulting mechanical and electrical properties. ...Well-dispersed ceramic-GO powders were fabricated using a colloidal processing route. Dense composites were obtained via spark plasma sintering, a technique that has the ability to reduce GO to graphene in situ during the sintering process. The mechanical properties of the sintered composites were investigated. The composite with only a small amount of graphene (0.5 vol.%) showed the highest flexural strength (904±56MPa), fracture toughness (10.6±0.3MPa·m1/2) and hardness (22±0.8GPa) with an extremely good dispersion of graphene within the ceramic matrix. In addition to these exceptional mechanical properties, the sintered composites also showed high electrical conductivity, which allows the compacts to be machined using electrical discharge machining and thus facilitates the fabrication of ceramic components with sophisticated shapes while reducing machining costs.
In the present work, the dry sliding behavior of a graphene/alumina composite material was studied against alumina in air. The tests were carried out in a reciprocating wear tester with an applied ...load of 20N, a sliding speed of 0.06ms−1 and a sliding distance of up to 10km. Under the testing conditions, the graphene/ceramic composite showed approximately half the wear rate and a 10% lower friction coefficient than the monolithic alumina. It has been found that this behavior is related to the presence of graphene platelets adhered to the surface of friction that form a self-lubricating layer which provides enough lubrication in order to reduce both wear rate and friction coefficient, as compared to the alumina/alumina tribological system.
Calcium hexaluminate (CA6) forms a broad range of solid solutions by substitution of Al
3+
with other cations such as, for example, Fe, Co, Mn, etc. Solid solutions of CA6 with magnetic ions have ...attracted interest because they allow designing the magnetic behavior depending on the composition of each solid solution. In this paper, we have studied materials pertaining to an area of the CaO–Al
2
O
3
–Fe
2
O
3
ternary phase diagram that is potentially interesting, but which has not been too much explored so far. We report on various synthesis methods of calcium hexaluminate with iron in solid solution. The percentages of iron introduced have been varied in order to determine the maximum percentage of iron that can enter into solid solution in the calcium hexaluminate such that the materials obtained exhibit magnetic behavior.
Graphical Abstract
Exploring the limits of Fe
3+
solid solution in calcium hexaluminate.
In this study a phosphate-free glass-ceramic porous scaffold was synthesized by a three-step methodology involving slurry preparation, induction of porosity by surfactant-assisted foaming following ...by freeze-drying and sintering. This inorganic scaffold was characterized by X-ray diffraction, scanning electron microscope (SEM), degradation and bioactivity. Thermal treatment at 750 °C showed two new crystalline phases, combeite and nepheline, into the glassy matrix responsible for its properties. The cell response of the scaffold was also evaluated for using as a bone graft substitute. A commercial Biphasic Calcium Phosphate, BCP, scaffold was assessed in parallel as reference material. Microstructures obtained by SEM showed the presence of macro, meso and microporosity. The glass-ceramic scaffold possesses an interconnected porosity around 31% with a crack-pore system that promote the protein adsorption and cell attachment. Glass-ceramic scaffold with high concentration of calcium ions shows an antimicrobial behavior against Escherichia coli after 24 h of contact. Nepheline phase present in the glass-ceramic structure is responsible for its high mechanical properties being around 87 MPa. Glass-ceramic scaffold promotes greater protein adsorption and therefore the attachment, spreading and osteodifferentiation of Adipose Derived Stem Cells than BCP scaffold. A higher calcification was induced by glass-ceramic scaffold compared to reference BCP material.
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