Molecular dynamics trajectories for 630 coarse-grained drug-membrane permeations

The permeation of small-molecule drugs across a phospholipid membrane bears much interest both in the pharmaceutical sciences and in physical chemistry. Connecting the chemistry of the drug and the lipids to the resulting thermodynamic properties remains of immediate importance. Here we report molecular dynamics (MD) simulation trajectories using the coarse-grained (CG) Martini force field. A wide, representative coverage of chemistry is provided: across solutes-exhaustively enumerating all 105 CG dimers-and across six phospholipids. For each combination, umbrella-sampling simulations provide detailed structural information of the solute at all depths from the bilayer midplane to bulk water, allowing a precise reconstruction of the potential of mean force. Overall, the present database contains trajectories from 15,120 MD simulations. This database may serve the further identification of structure-property relationships between compound chemistry and drug permeability

Protective role of natural and semi-synthetic tocopherols on TNFα-induced ros production and ICAM-1 and Cl-2 expression in ht29 intestinal epithelial cells

Vitamin E, a fat-soluble compound, possesses both antioxidant and non-antioxidant properties. In this study we evaluated, in intestinal HT29 cells, the role of natural tocopherols, α-Toc and δ-Toc, and two semi-synthetic derivatives, namely bis-δ-Toc sulfide (δ-Toc)2S and bis-δ-Toc disulfide (δ-Toc)2S2, on TNFα-induced oxidative stress, and intercellular adhesion molecule-1 (ICAM-1) and claudin-2 (Cl-2) expression. The role of tocopherols was compared to that of N-acetylcysteine (NAC), an antioxidant precursor of glutathione synthesis. The results show that all tocopherol containing derivatives used, prevented TNFα-induced oxidative stress and the increase of ICAM-1 and Cl-2 expression, and that (δ-Toc)2S and (δ-Toc)2S2 are more effective than δ-Toc and α-Toc. The beneficial effects demonstrated were due to tocopherol antioxidant properties, but suppression of TNFα-induced Cl-2 expression seems not only to be related with antioxidant ability. Indeed, while ICAM-1 expression is strongly related to the intracellular redox state, Cl-2 expression is TNFα-up-regulated by both redox and non-redox dependent mechanisms. Since ICAM-1 and Cl-2 increase intestinal bowel diseases, and cause excessive recruitment of immune cells and alteration of the intestinal barrier, natural and, above all, semi-synthetic tocopherols may have a potential role as a therapeutic support against intestinal chronic inflammation, in which TNFα represents an important proinflammatory mediator

Gravity map of the isla Grande de Tierra de Fuego, and morphology of Lago Fagnano

A complete Bouguer gravity map of the central-eastern part of the Isla Grande de Tierra del Fuego, and a general bathymetric chart of the Lago Fagnano have been realized, on the basis of a series of field geophysical surveys carried out on the Island since 1998. The regional gravity anomaly trend onshore shows a progressive negative gradient from N to S. Distinct, broadly E-W-trending gravity minima are superimposed on this regional negative gradient. They follow the main trace of the Magallanes-Fagnano fault system, which represents the western segment of the left-lateral South America-Scotia transform plate boundary. The gravity minima reflect the presence in the subsurface of restricted and elongated basins developed within the principal displacement zone of the fault system. A relative positive gravity maximum is located just at the SE corner of the Lago Fagnano, and represents the response of a partially exposed crystalline body, occupying an area 3 x 3 km wide. A 2D vertical crustal model has been constructed, combining gravity data inversion and geological information available for the central-eastern region of Lago Fagnano. The bathymetric map of the Lago Fagnano delineates the main morphological features of this 110-km-long, 7-km-wide lake, the largest of Isla Grande. The floor is divided into distinct parts, which suggests that the basin is composed of different sub-basins. In most areas, the basin floor is highly asymmetric in shape, with flat depocentral areas. The most pronounced asymmetry of the basin is seen in the eastern end of the lake, where there is also the deepest depression. The steeper slope of the basin, along the northern shore of the Lago Fagnano, also coincides with the most pronounced regional topographic gradient. The general gravimetric and morphological features of the investigated region are here discussed

Synthesis and characterization of multifunctional nanovesicles composed of POPC lipid molecules for nuclear imaging

The integration of nuclear imaging analysis with nanomedicine has tremendously grown and represents a valid and powerful tool for the development and clinical translation of drug delivery systems. Among the various types of nanostructures used as drug carriers, nanovesicles represent intriguing platforms due to their capability to entrap both lipophilic and hydrophilic agents, and their well-known biocompatibility and biodegradability. In this respect, here we present the development of a labelling procedure of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3- phosphocholine)-based liposomes incorporating an ad hoc designed lipophilic NOTA (1, 4, 7- triazacyclononane-1, 4, 7-triacetic acid) analogue, derivatized with an oleic acid residue, able to bind the positron emitter gallium-68(III). Based on POPC features, the optimal conditions for liposome labelling were studied with the aim of optimizing the Ga(III) incorporation and obtaining a significant radiochemical yield. The data presented in this work demonstrate the feasibility of the labelling procedure on POPC liposomes co-formulated with the ad hoc designed NOTA analogue. We thus provided a critical insight into the practical aspects of the development of vesicles for theranostic approaches, which in principle can be extended to other nanosystems exploiting a variety of bioconjugation protocols

Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-, Cefiderocol-Resistant ST-512 Klebsiella pneumoniae-Producing KPC-31, a D179Y Variant of KPC-3

A 68-year-old man had recurrent bacteremia by Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae resistant to ceftazidime-avibactam and cefiderocol. The sequencing of a target region showed that it harbored a KPC-3 variant enzyme (D179Y; KPC-31), which confers resistance to ceftazidime-avibactam and restores meropenem susceptibility. The patient was successfully treated with meropenem-vaborbactam

Rapid detection of intestinal carriage of Klebsiella pneumoniae producing KPC carbapenemase during an outbreak

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