Cutaneous Adverse Events Associated with Interferon-β Treatment of Multiple Sclerosis

Interferons are widely used platform therapies as disease-modifying treatment of patients with multiple sclerosis. Although interferons are usually safe and well tolerated, they frequently cause dermatological side effects. Here, we present a multiple sclerosis (MS) patient treated with interferon-β who developed new-onset psoriasis. Both her MS as well as her psoriasis finally responded to treatment with fumarates. This case illustrates that interferons not only cause local but also systemic adverse events of the skin. These systemic side effects might indicate that the Th17/IL-17 axis plays a prominent role in the immunopathogenesis of this individual case and that the autoimmune process might be deteriorated by further administration of interferons. In conclusion, we think that neurologists should be aware of systemic cutaneous side effects and have a closer look on interferon-associated skin lesions. Detection of psoriasiform lesions might indicate that interferons are probably not beneficial in the individual situation. We suggest that skin lesions may serve as biomarkers to allocate MS patients to adequate disease-modifying drugs.     

Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury

Background and Aims: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4^−/− mice with deficiency of the hepatobiliary phospholipid transporter. Methods: Total RNA was extracted from wild-type (WT, C57BL/6J) and Abcb4⁻/⁻ (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; n = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KO-EtOH groups; n = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; n = 31) and healthy controls (n = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments. Results: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic Cyp7a1 levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (Fgfr1), Fgfr4, Farnesoid X-activated receptor (Fxr), and Small heterodimer partner (Shp) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed Cyp7a1 in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ. Conclusions: The simultaneous upregulation of FGF21 and downregulation of Cyp7a1 expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic Shp and Fxr levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of Cyp7a1 expressions while circulating FGF15 and hepatic Shp and Fxr levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1.     

Impact of coagulation and adsorption on DOC fractions of secondary effluent and resulting fouling behaviour in ultrafiltration

Membrane fouling by macromolecular dissolved organic compounds is still a fundamental drawback in low-pressure membrane filtration of secondary effluent. In this study, pre-treatment of secondary effluent by coagulation and/or adsorption was investigated in terms of removal of different dissolved organic carbon (DOC) fractions, especially macromolecular substances. DOC fractionation has been characterised by size exclusion chromatography. Adsorption tests using four commercially available activated carbons yielded a removal of small as well as larger organic compounds, revealing differences in the affinity towards macromolecules depending on the type of applied activated carbon. By contrast, coagulation removed predominantly larger molecules, i.e., biopolymers and humic substances. In terms of DOC reduction, the coagulant ferric chloride was superior to aluminium chloride. A combination of coagulation and adsorption resulted in the addition of individual removal efficiencies, suggesting that different fractions of organic compounds were involved in each of the processes. After removal of macromolecular organic compounds either by coagulation or by adsorption, a significant reduction of membrane fouling was observed in tests using two different types of ultrafiltration flat-sheet membranes in 20-h cross-flow filtration tests.     

Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase

Enzymes are effective biological catalysts that accelerate almost all metabolic reactions in living organisms. Synthetic modulators of enzymes are useful tools for the study of enzymatic reactions and can provide starting points for the design of new drugs. Here, we report on the discovery of a class of biologically active compounds that covalently modifies lysine residues in human liver pyruvate kinase (PKL), leading to allosteric activation of the enzyme (EC₅₀=0.29 μM). Surprisingly, the allosteric activation control point resides on the lysine residue K282 present in the catalytic site of PKL. These findings were confirmed by structural data, MS/MS experiments, and molecular modelling studies. Altogether, our study provides a molecular basis for the activation mechanism and establishes a framework for further development of human liver pyruvate kinase covalent activators.     

Interaction of titanium diboride/boron nitride evaporation boats with aluminium

Hexagonal boron nitride/titanium diboride composites are widely used as evaporation boats for aluminium deposition to produce functional and decorative layers on different target materials. The lifetime of such a material is limited mainly by the interaction of the metal with the ceramic substrate, but the corrosion mechanism has still not yet been thoroughly investigated and understood. In this article the corrosion mechanism for the evaporation boats used was investigated using thermodynamic calculations, FESEM, EDX and XRD phase analysis. The analysis showed that hexagonal boron nitride (hBN), which is thermodynamically less stable than TiB₂, is passivated during the application process through the formation of AlN surface layers, whereas the thermodynamically more stable TiB₂ phase dissolves and Ti-rich components precipitate in cooler regions of the evaporation boats.     

Near-zero triangular location through time-slotted mobility prediction

To setup efficient wireless mesh networks, it is fundamental to limit the overhead needed to localize a mobile user. A promising approach is to rely on a rendezvous-based location system where the current location of a mobile node is stored at specific nodes called locators. Nevertheless, such a solution has a drawback, which happens when the locator is far from the source–destination shortest path. This results in a triangular location problem and consequently in increased overhead of signaling messages. One solution to prevent this problem would be to place the locator as close as possible to the mobile node. This requires however to predict the mobile node’s location at all times. To obtain such information, we define a mobility prediction model (an agenda) that, for each node, specifies the mesh router that is likely to be the closest to the mobile node at specific time periods. The location service that we propose formalizes the integration of the agenda with the management of location servers in a coherent and self-organized fashion. To evaluate the performance of our system compared to traditional approaches, we use two real-life mobility datasets of Wi-Fi devices in the Dartmouth campus and Taxicabs in the bay area of San Francisco. We show that our strategy significantly outperforms traditional solutions; we obtain gains ranging from 39 to 72% compared to the centralized scheme and more than 35% compared to a traditional rendezvous-based solution.     

Kinetics of rare earth incorporation and its role in densification and microstructure formation of α-Sialon

The reproducible sintering and microstructure formation of α- and α/β-Sialons is a precondition for the production of such materials with reproducible properties.The Rietveld method was used for quantitative analysis of the phase composition and the kinetics of incorporation of the rare earth into the α-Sialon structure. The analysis showed that in the early stages of sintering more rare earth cations were incorporated into the grains than would be expected from the equilibrium conditions. This was observed for all investigated rare earths (Y, Nd and Yb) with different ionic radii. The consequences for sintering and microstructure formation are the fast disappearing of the transient liquid and the formation of polytypes. The use of excess of rare earth in comparison to the stoichiometric Sialon composition results in a stable residual liquid. It allows reproducible densification, anisotropic grain growth and materials with high fracture toughness.