6-(4-Chloro­phen­yl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-carbaldehyde

The 4-chloro­phenyl residue in the title compound, C20H16ClNO, is oriented at a dihedral angle of 53.6 (3)° towards the phenyl ring and 42.0 (9)° towards the pyrrole ring of the pyrrolizine template. The phenyl ring is oriented at a dihedral angle of 45.4 (4)° towards the pyrrole ring

6-(4-Meth­oxy­phen­yl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-carbaldehyde

The 4-meth­oxy­phenyl residue in the title compound, C21H19NO2, is oriented at a dihedral angle of 54.6 (5)° with respect to the phenyl ring and at a dihedral angle of 52.5 (8)° with respect to the pyrrole ring of the pyrrolizine system. The phenyl ring is oriented at a dihedral angle of 36.2 (5)° with respect to the pyrrole ring. The meth­oxy group makes a C—C—O—C torsion angle of 3.8 (9)° with the attached benzene ring

Application of magnetic resonance imaging in transgenic and chemical mouse models of hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The molecular mechanisms underlying hepatocarcinogenesis are still poorly understood. Genetically modified mice are powerful tools to further investigate the mechanisms of HCC development. However, this approach is limited due to the lack of non-invasive detection methods in small rodents. The aim of this study was to establish a protocol for the non-invasive analysis of hepatocarcinogenesis in transgenic mice using a clinical 1.5 Tesla Magnetic Resonance Imaging scanner.</p> <p>Results</p> <p>As a model system we used hepatocyte-specific c-myc transgenic mice developing hepatocellular carcinoma at the age of 12-15 months. The scans of the murine livers included axial T2-weighted turbo-spin echo (TSE) images, axial T1-weighted and contrast enhanced T1-weighted gradient echo (fast field echo, FFE) and sagittal true Fast Imaging with Steady state Precession (true-FISP) images. Application of contrast agent was performed via tail vein-catheter and confirmed by evaluation of the altered longitudinal relaxation T1 time before and after application. Through technical adaptation and optimization we could detect murine liver lesions with a minimum diameter of approximately 2 mm and provided histopathological evidence that these MR findings correspond to hepatocellular carcinoma. Tumor growth was repeatedly measured using sequential MRI with intervals of 5 weeks and subsequent volumetric analysis facilitating direct comparison of tumor progression between individual animals. We finally demonstrated that our protocol is also applicable in the widely- used chemical model of N-nitrosodiethylamine-induced hepatocarcinogenesis.</p> <p>Conclusion</p> <p>Our protocol allows the non-invasive, early detection of HCC and the subsequent continuous monitoring of liver tumorgenesis in transgenic mice thereby facilitating future investigations of transgenic tumor mouse models of the liver.</p

Emotion recognition from faces with in- and out-group features in patients with depression

Background Previous research has shown that context (e.g. culture) can have an impact on speed and accuracy when identifying facial expressions of emotion. Patients with a major depressive disorder (MDD) are known to have deficits in the identification of facial expressions, tending to give rather stereotypical judgments. While healthy individuals perceive situations which conflict with their own cultural values more negatively, this pattern would be even stronger in MDD patients, as their altered mood results in stronger biases. In this study we investigate the effect of cultural contextual cues on emotion identification in depression. Methods Emotional faces were presented for 100 ms to 34 patients with an MDD and matched controls. Stimulus faces were either covered by a cap and scarf (in-group condition) or by an Islamic headdress (niqab; out-group condition). Speed and accuracy were evaluated. Results Results showed that across groups, fearful faces were identified faster and with higher accuracy in the out-group than in the in-group condition. Sadness was also identified more accurately in the out-group condition. In comparison, happy faces were more accurately (and tended to be faster) identified in the in-group condition. Furthermore, MDD patients were slower, yet not more accurate in identifying expressions of emotion compared to controls. Limitations All patients were on pharmacological treatment. Participants’ political orientation was not included. The experiment differs from real life situations. Conclusion While our results underline findings that cultural context has a general impact on emotion identification, this effect was not found to be more prominent in patients with MDD.NWO016-155-082Action Contro

Structural Analysis of a Nitrogenase Iron Protein from Methanosarcina acetivorans: Implications for CO2 Capture by a Surface-Exposed [Fe4S4] Cluster.

Nitrogenase iron (Fe) proteins reduce CO2 to CO and/or hydrocarbons under ambient conditions. Here, we report a 2.4-Å crystal structure of the Fe protein from Methanosarcina acetivorans (MaNifH), which is generated in the presence of a reductant, dithionite, and an alternative CO2 source, bicarbonate. Structural analysis of this methanogen Fe protein species suggests that CO2 is possibly captured in an unactivated, linear conformation near the [Fe4S4] cluster of MaNifH by a conserved arginine (Arg) pair in a concerted and, possibly, asymmetric manner. Density functional theory calculations and mutational analyses provide further support for the capture of CO2 on MaNifH while suggesting a possible role of Arg in the initial coordination of CO2 via hydrogen bonding and electrostatic interactions. These results provide a useful framework for further mechanistic investigations of CO2 activation by a surface-exposed [Fe4S4] cluster, which may facilitate future development of FeS catalysts for ambient conversion of CO2 into valuable chemical commodities.IMPORTANCE This work reports the crystal structure of a previously uncharacterized Fe protein from a methanogenic organism, which provides important insights into the structural properties of the less-characterized, yet highly interesting archaeal nitrogenase enzymes. Moreover, the structure-derived implications for CO2 capture by a surface-exposed [Fe4S4] cluster point to the possibility of developing novel strategies for CO2 sequestration while providing the initial insights into the unique mechanism of FeS-based CO2 activation

An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behavior

Serpins are important regulators of proteolytic pathways with an antiprotease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an intermolecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of many pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-Antitrypsin (α1-AT) polymerisation in cells. Here, we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39 and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A - on the opposite face of the molecule - more liable to adopt an 'open' state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of a preformed serpin-enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the 'open' state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for a rational design of ligands that is able to dynamically influence α1-AT polymerisation

Expression of the Metalloproteinase ADAM8 Is Upregulated in Liver Inflammation Models and Enhances Cytokine Release In Vitro

Acute and chronic liver inflammation is driven by cytokine and chemokine release from various cell types in the liver. Here, we report that the induction of inflammatory mediators is associated with a yet undescribed upregulation of the metalloproteinase ADAM8 in different murine hepatitis models. We further show the importance of ADAM8 expression for the production of inflammatory mediators in cultured liver cells. As a model of acute inflammation, we investigated liver tissue from lipopolysaccharide- (LPS-) treated mice in which ADAM8 expression was markedly upregulated compared to control mice. In vitro, stimulation with LPS enhanced ADAM8 expression in murine and human endothelial and hepatoma cell lines as well as in primary murine hepatocytes. The enhanced ADAM8 expression was associated with an upregulation of TNF-α and IL-6 expression and release. Inhibition studies indicate that the cytokine response of hepatoma cells to LPS depends on the activity of ADAM8 and that signalling by TNF-α can contribute to these ADAM8-dependent effects. The role of ADAM8 was further confirmed with primary hepatocytes from ADAM8 knockout mice in which TNF-α and IL-6 induction and release were considerably attenuated. As a model of chronic liver injury, we studied liver tissue from mice undergoing high-fat diet-induced steatohepatitis and again observed upregulation of ADAM8 mRNA expression compared to healthy controls. In vitro, ADAM8 expression was upregulated in hepatoma, endothelial, and stellate cell lines by various mediators of steatohepatitis including fatty acid (linoleic-oleic acid), IL-1β, TNF-α, IFN-γ, and TGF-β. Upregulation of ADAM8 was associated with the induction and release of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CX3CL1). Finally, knockdown of ADAM8 expression in all tested cell types attenuated the release of these mediators. Thus, ADAM8 is upregulated in acute and chronic liver inflammation and is able to promote inflammation by enhancing expression and release of inflammatory mediators

Innovative Thermal Management Concepts and Material Solutions for Future Space Vehicles

When entering a planetary atmosphere, space vehicles are exposed to extreme thermal loads. To protect the vehicle’s interior, a thermal protection system is required. Future aerospace transportation demands solutions that exceed the performance of current systems and up-to-date material limits. Therefore, new and disruptive solutions must be envisaged to meet those extreme conditions. In the search of new solutions for sharp leading edges of future hypersonic reentry or transport vehicles, the THOR project, composed of eight European organizations (industries, research centers, and universities) and one Japanese Agency (Japan Aerospace Exploration Agency), is actively working on definition, design, implementation, and simulation of new passive and active thermal management solutions and their verification in relevant environments (high-enthalpy facilities). This paper provides an overview of the recent developments on the four concepts that are targeted in the project, applying different physical methodologies: 1) passive cooling using highly conductive carbon-based fibers, 2) passive cooling with intensive internal radiative exchange, 3) active cooling based on convection heat transfer using a ceramic sandwich/thermal protection system with ceramic foams/lattices, and 4) active transpiration cooling of external surfaces. Details on these thermal management concepts, requirements from end users, and test configurations, as well as results from experimental and numerical verification, are given

Relevance of the H2 + O reaction pathway for the surface formation of interstellar water. Combined experimental and modeling study

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