Selective inhibition of intestinal guanosine 3,5-cyclic monophosphate signaling by small-molecule protein kinase inhibitors

The guanosine 3,5-cyclic monophosphate (cGMP)-dependent protein kinase II (cGKII) serine/threonine kinase relays signaling through guanylyl cyclase C (GCC) to control intestinal fluid homeostasis. Here, we report the discovery of small-molecule inhibitors of cGKII. These inhibitors were imidazole-aminopyrimidines, which blocked recombinant human cGKII at submicromolar concentrations but exhibited comparatively little activity toward the phylogenetically related protein kinases cGKI and cAMP-dependent protein kinase (PKA). Whereas aminopyrimidyl motifs are common in protein kinase inhibitors, molecular modeling of these imidazole-aminopyrimidines in the ATP-binding pocket of cGKII indicated an unconventional binding mode that directs their amine substituent into a narrow pocket delineated by hydrophobic residues of the hinge and the C-helix. Crucially, this set of residues included the Leu-530 gatekeeper, which is not conserved in cGKI and PKA. In intestinal organoids, these compounds blocked cGKII-dependent phosphorylation of the vasodilator-stimulated phosphoprotein (VASP). In mouse small intestinal tissue, cGKII inhibition significantly attenuated the anion secretory response provoked by the GCC-activating bacterial heat-stable toxin (STa), a frequent cause of infectious secretory diarrhea. In contrast, both PKA-dependent VASP phosphorylation and intestinal anion secretion were unaffected by treatment with these compounds, whereas experiments with T84 cells indicated that they weakly inhibit the activity of cAMP-hydrolyzing phosphodiesterases. As these protein kinase inhibitors are the first to display selective inhibition of cGKII, they may expedite research on cGMP signaling and may aid future development of therapeutics for managing diarrheal disease and other pathogenic syndromes that involve cGKII

Adsorption of short-chain tetraalkylammonium bromide on silica

The adsorption of tetraalkylammonium (TAA) ions on silica shifts the isoelec. point to higher pH values. The IEP shift increases with increasing alkyl chain length. Also, tetraethylammonium (TEA) and tetrapropylammonium (TPA) ions can be adsorbed in larger amts. than tetramethylammonium (TMA) ions. The chemisorption of TAA ions can be explained by assuming an attraction between hydrophobically hydrated regions around surface siloxane bridges and around the TAA ions. The adsorption data of TMA ions are compatible with the stimulated adsorption model. [on SciFinder (R)

Treatment of renal sarcoidosis: is there a guideline?: overview of the different treatment options

Sarcoidosis is a multisystem granulomatous disease of unknown aetiology characterized by the presence of noncaseating granulomas. It may affect any organ including the kidney. A disordered calcium metabolism is most often responsible for the development of renal failure. Granulomatous interstitial nephritis is the most typical histological finding, but it rarely leads to renal insufficiency. Since development of renal insufficiency in sarcoidosis is uncommon, we lack large (randomized) trials concerning the treatment of this disorder. We gather most information from case reports and small series. Our knowledge of pulmonary sarcoidosis is more comprehensive. It is, however, impossible to treat renal manifestations identically because some of the drugs used in pulmonary sarcoidosis are nephrotoxic. Moreover, renal sarcoidosis is a specific entity with its own characteristics and response to therapy. A guideline for treatment is currently missing. Based on a review of the literature, we present an overview of the different treatment options to promote a more uniform and scrutinized approach of this disease. Hypercalcaemia and hypercalciuria can be treated with corticosteroids, (hydroxy) chloroquine or ketoconazole. Preventive measures play a supportive role. In granulomatous interstitial nephritis, glucocorticoids are the standard of care. In patients with failure of or a contraindication to corticosteroids or in those patients who need a high maintenance dose of corticosteroids, azathioprine or mycophenolate mofetil can be used. TNF-alpha inhibitors are useful in case of steroid-resistant sarcoidosis or in patients who develop severe steroid toxicity. With increasing insight in the pathogenesis of sarcoidosis, other immunosuppressive drugs have been proposed, but more research is necessary before their routine use can be advocated

Vergelijkende studie van de simulatieprogramma's voor chemischeprocessen Aspen Plus en Flowtran

KULeuven Campusbibliotheek Exacte Wetenschappen / UCL - Université Catholique de LouvainSIGLEBEBelgiu

Remote Thermoelastic Characterization of Candidate Structural and Protective Coatings for Lead-Bismuth Eutectic Cooled Nuclear Reactors

© 2019 by the authors. A laser ultrasonics approach to remotely characterize the elastic and thermal properties of a coating-substrate structure, used to protect fuel claddings in lead-bismuth eutectic cooled nuclear reactors, is presented and validated with experimental results. A transient grating geometry is used for multiple wavelength excitation of thermoelastic displacements, and laser beam deflection for detection. The value of Young's modulus of the coating layer as calculated from the coating's Rayleigh velocity of 190 ± 50 GPa is in accordance with a nano-indentation measurement. Using a priori knowledge concerning the density and elastic parameters of the coating and substrate, scanning the sample allows the obtaining of a coating thickness map in a fully remote, all-optical way, with an accuracy of about 4 microns for a coating of around 20-micron average thickness. Analyzing the transient thermal grating decay yields a thermal diffusivity value of (5.0 ± 1.6) × 10 -6 m 2 /s, in the range of low-carbon steels. The consistency of the results infers that the all-optical laser ultrasonics approach should be feasible for remote inspection of the quality of optically rough coated claddings in the harsh environment of a nuclear reactor.status: publishe

Method and system for forming a metallic structure

Method of forming a metallic structure (2) in a micro-machined recess that is provided in a surface of a semiconductor substrate (8). The method comprises positioning a protrusion (10) of an apparatus for depositing the metallic structure at least partly inside the recess, thus partly occupying the recess with the protrusion and defining in the recess a gap (14) along the protrusion. The method comprises driving a deposition fluid (20) through the gap in the recess along the protrusion. The method comprises growing in the gap the metallic structure by depositing metal ions contained by the deposition fluid. The method comprises moving the protrusion and the substrate relative to each other so that the protrusion, while being positioned in the recess, moves relative to the recess in a direction out of the recess, thus giving way for the growing of the metallic structure, and forming the metallic structure in the recess

Remote Thermoelastic Characterization of Candidate Structural and Protective Coatings for Lead-Bismuth Eutectic Cooled Nuclear Reactors

A laser ultrasonics approach to remotely characterize the elastic and thermal properties of a coating-substrate structure, used to protect fuel claddings in lead-bismuth eutectic cooled nuclear reactors, is presented and validated with experimental results. A transient grating geometry is used for multiple wavelength excitation of thermoelastic displacements, and laser beam deflection for detection. The value of Young’s modulus of the coating layer as calculated from the coating’s Rayleigh velocity of 190 ± 50 GPa is in accordance with a nano-indentation measurement. Using a priori knowledge concerning the density and elastic parameters of the coating and substrate, scanning the sample allows the obtaining of a coating thickness map in a fully remote, all-optical way, with an accuracy of about 4 microns for a coating of around 20-micron average thickness. Analyzing the transient thermal grating decay yields a thermal diffusivity value of ( 5.0 ± 1.6 ) × 10 − 6 m 2 /s, in the range of low-carbon steels. The consistency of the results infers that the all-optical laser ultrasonics approach should be feasible for remote inspection of the quality of optically rough coated claddings in the harsh environment of a nuclear reactor