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International audience; Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology for which there are no approved therapeutic options. Patients with PSC display changes in gut microbiota and in bile acid (BA) composition; however, the contribution of these alterations to disease pathogenesis remains controversial. Here we identify a role for microbiota-dependent changes in BA synthesis that modulates PSC pathophysiology. In a genetic mouse model of PSC, we show that loss of microbiota-mediated negative feedback control of BA synthesis results in increased hepatic BA concentrations, disruption of bile duct barrier function and, consequently, fatal liver injury. We further show that these changes are dependent on decreased BA signalling to the farnesoid X receptor, which modulates the activity of the rate-limiting enzyme in BA synthesis, CYP7A1. Moreover, patients with advanced stages of PSC show suppressed BA synthesis as measured by serum C4 levels, which is associated with poor disease prognosis. Our preclinical data highlight the microbiota-dependent dynamics of BA metabolism in cholestatic liver disease, which could be important for future therapies targeting BA and gut microbiome interactions, and identify C4 as a potential biomarker to functionally stratify patients with PSC and predict disease outcomes.

Cells : open access journal 10(10), 2618 (2021). doi:10.3390/cells10102618 special issue: "Topical Collection "The Role of NLRP3 in Health and Disease" / Edited by: Prof. Dr. Alexander Wree, Collection Editor", Published by MDPI, Basel

Fouling issues in steam crackers may arise due to a number of reasons, including emulsion formation in the quench water tower. Freeze-drying according to a protocol developed in-house was used to extract species potentially capable of stabilizing emulsions from process water sampled from a quench tower. Such species were subsequently fractionated into solubility classes: water soluble, and soluble in organic solvents (polar and apolar). Liquid chromatography/mass spectrometry analyses indicated differences in the chemical composition of these fractions, with molecules bigger and richer in oxygen in the fraction soluble in polar organic solvents compared to those detected in the water soluble fraction. Bottle tests demonstrated that the interfacial material soluble in polar organic solvents was the most effective in stabilizing water-in-gasoline and gasoline-in-water emulsions. When the water soluble fraction was added to these stable emulsions it acted as demulsifier, with the most marked effects observed at low pH. In the absence of the water soluble fraction emulsion stability was largely pH-independent. The role of electrostatic forces in emulsion stabilization was investigated by conducting zeta potential measurements. With the organic soluble fraction only added to the oil phase and at pH 5.5, emulsions were stable and the zeta potential was close to zero, proving that electrostatic forces did not play a role in stabilizing this system. With the water soluble fraction added to the water phase and at alkaline pH, emulsions were stable and the zeta potential was negative, suggesting that electrostatic stabilization mechanisms cannot be discounted in the presence of the water soluble fraction. Scanning Electron Microscopy (SEM)/Energy Dispersive X-Ray Spectroscopy (EDX) were used to probe the morphology and elemental composition of the Langmuir-Blodgett films extracted from the gasoline-water interface. SEM images highlighted the presence of particles at the gasoline-water interface, suggesting Pickering stabilization mechanisms. Dynamic interfacial tension measurements showed that the decrease of the interfacial tension measured for gasoline-water interfaces upon addition of interfacial material was relatively low and similar for all fractions, supporting this hypothesis. SEM/EDX data further reveal the strong correlation between interfacial film composition and emulsion stability, with high densities of particles containing sulfur and iron associated with significant emulsion stability. The compressional visco-elastic moduli of interfacial films were determined using a pulsating drop rheometer. Measurements were done at pH 5.5 and 8.5, with the individual solubility fractions added. Film rigidity was similar with all fractions, indicating that it did not dictate the differences in their stabilizing properties.

ObjectiveThere is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut–liver crosstalk for CLD in the murine Mdr2 knockout(Mdr2−/−)model resembling human primary sclerosing cholangitis (PSC).DesignMaleMdr2−/−,Mdr2−/−crossed with hepatocyte-specific deletion of caspase-8 (Mdr2−/−/Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role ofMdr2−/−-associated intestinal dysbiosis was studied by microbiota transfer experiments.ResultsMdr2−/−mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut–liver axis. Intestinal dysbiosis inMdr2−/−mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer ofMdr2−/−microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.ConclusionsMDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

Vinyl monomers such as styrene may undergo undesired polymerization reactions during the industrial processes in which they are synthesized and purified. To avoid this undesired phenomenon, polymerization inhibitors such as (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) and its analogues can be used. An inhibitor and stability screening setup built in-house was used to compare the effectiveness of thirteen TEMPO analogues in inhibiting the polymerization of styrene in toluene at 130 °C. The data show that the substituent in the 4′-position in the cyclic structure of the TEMPO molecules strongly influenced their effectiveness in inhibiting polymerization. Computational methods based on the density functional theory (DFT) approach have been utilized to understand the reactivity of the TEMPO analogues. The global reactivity descriptors derived from the DFT calculations indicate that the TEMPO analogues with high global electrophilicity are more effective than those with low global electrophilicity in inhibiting the polymerization. The data suggest that the solubility of the TEMPO analogues in toluene and the keto–enol tautomerism of certain molecules may also affect their ability to inhibit styrene polymerization.

The amide bond is a versatile functional group and its directional hydrogen-bonding capabilities are widely applied in, for example, supramolecular chemistry. The potential of the thioamide bond, in contrast, is virtually unexplored as a structuring moiety in hydrogen-bonding-based self-assembling systems. We report herein the synthesis and characterisation of a new self-assembling motif comprising thioamides to induce directional hydrogen bonding. N,N',N''-Trialkylbenzene-1,3,5-tris(carbothioamide)s (thioBTAs) with either achiral or chiral side-chains have been readily obtained by treating their amide-based precursors with P2S5. The thioBTAs showed thermotropic liquid crystalline behaviour and a columnar mesophase was assigned. IR spectroscopy revealed that strong, three-fold, intermolecular hydrogen-bonding interactions stabilise the columnar structures. In apolar alkane solutions, thioBTAs self-assemble into one-dimensional, helical supramolecular polymers stabilised by three-fold hydrogen bonding. Concentration- and temperature-dependent self-assembly studies performed by using a combination of UV and CD spectroscopy demonstrated a cooperative supramolecular polymerisation mechanism and a strong amplification of supramolecular chirality. The high dipole moment of the thioamide bond in combination with the anisotropic shape of the resulting cylindrical aggregate gives rise to sufficiently strong depolarised light scattering to enable depolarised dynamic light scattering (DDLS) experiments in dilute alkane solution. The rotational and translational diffusion coefficients, D(trans) and D(rot), were obtained from the DDLS measurements, and the average length, L, and diameter, d, of the thioBTA aggregates were derived (L = 490 nm and d = 3.6 nm). These measured values are in good agreement with the value L(w) = 755 nm obtained from fitting the temperature-dependent CD data by using a recently developed equilibrium model. This experimental verification validates our common practice for determining the length of BTA-based supramolecular polymers from model fits to experimental CD data. The ability of thioamides to induce cooperative supramolecular polymerisation makes them effective and broadly applicable in supramolecular chemistry.

A common finite element modeling approach for buried pipelines is the combined use of beam and spring elements. Typical loads are soil settlements, temperature variations, internal pressures, neutral topsoil loads and traffic loads. The beam elements represent the pipeline; assemblies of spring elements represent the surrounding soil comprising an elasto-plastic bedding and friction. The choice for such finite element models is a pragmatic one. The models are relatively easy to construct and the analyses can be performed within reasonable calculation time on an average PC. From a mechanical point of view the problem of a buried pipeline subjected to subsidence, or an offshore pipeline subjected to sand waves, is of a full 3D nature. Beam elements and spring elements only partly incorporate full 3D effects. In practice the common finite element models are therefore enhanced to take into account 3D effects that would be missed otherwise. A major point is the distinction between beam action and cross sectional behavior of pipes in straight and curved sections and their mutual interaction.

A common finite element modeling approach for buried pipelines is the combined use of beam and spring elements. Typical loads are soil settlements, temperature variations, internal pressures, neutral topsoil weight load and traffic loads. The beam elements represent the pipeline; assemblies of spring elements represent the surrounding soil comprising an elastoplastic bedding with friction. The choice for such finite element models is a pragmatic one. The models are relatively easy to construct and the analyses can be performed within reasonable calculation time on an average PC. From a mechanical point of view the problem of a buried pipeline subjected to subsidence, or an offshore pipeline subjected to sand waves, is of a full 3D nature. Beam elements and spring elements only partly incorporate full 3D effects. In practice the common finite element models are therefore enhanced to take into account 3D effects that would be otherwise omitted. A major point is the distinction between beam action and cross sectional behavior of pipes in straight and curved sections and their mutual interaction. This paper discusses the pros and cons of two possible finite element approaches which deal with this full 3D problem. In the final example it is illustrated that the two approaches gives similar results for the relatively simple problem of a buried bended pipe subjected to a temperature load and internal pressure.Copyright © 2004 by ASME