Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice

While gap junctions mediate intercellular communication and support liver homeostasis, connexin hemichannels are preferentially opened by pathological stimuli, including inflammation and oxidative stress. The latter are essential features of non-alcoholic steatohepatitis. In this study, it was investigated whether connexin32 and connexin43 hemichannels play a role in non-alcoholic steatohepatitis. Mice were fed a choline-deficient high-fat diet or normal diet for 8 weeks. Thereafter, TAT-Gap24 or TAT-Gap19, specific inhibitors of hemichannels composed of connexin32 and connexin43, respectively, were administered for 2 weeks. Subsequently, histopathological examination was carried out and various indicators of inflammation, liver damage and oxidative stress were tested. In addition, whole transcriptome microarray analysis of liver tissue was performed. Channel specificity of TAT-Gap24 and TAT-Gap19 was examined in vitro by fluorescence recovery after photobleaching analysis and measurement of extracellular release of adenosine triphosphate. TAT-Gap24 and TAT-Gap19 were shown to be hemichannel-specific in cultured primary hepatocytes. Diet-fed animals treated with TAT-Gap24 or TAT-Gap19 displayed decreased amounts of liver lipids and inflammatory markers, and augmented levels of superoxide dismutase, which was supported by the microarray results. These findings show the involvement of connexin32 and connexin43 hemichannels in non-alcoholic steatohepatitis and, simultaneously, suggest a role as potential drug targets in non-alcoholic steatohepatitis

Connexin and pannexin (hemi) channels in the liver

The liver was among the first organs in which connexin proteins have been identified. Hepatocytes harbor connexin32 and connexin26, while non-parenchymal liver cells typically express connexin43. Connexins give rise to hemichannels, which dock with counterparts on adjacent cells to form gap junctions. Both hemichannels and gap junctions provide pathways for communication, via paracrine signaling or direct intercellular coupling, respectively. Over the years, hepatocellular gap junctions have been shown to regulate a number of liver-specific functions and to drive liver cell growth. In the last few years, it has become clear that connexin hemichannels are involved in liver cell death, particularly in hepatocyte apoptosis. This also holds true for hemichannels composed of pannexin1, a connexin-like protein recently identified in the liver. Moreover, pannexin1 hemichannels are key players in the regulation of hepatic inflammatory processes. The current paper provides a concise overview of the features of connexins, pannexins and their channels in the liver.This work was financially supported by the grants of the Agency for Innovation by Science and Technology in Flanders (IWT), the University Hospital of the Vrije Universiteit Brussel-Belgium (Willy Gepts Fonds UZ-VUB), the Fund for Scientific Research - Flanders (FWO grants G009514N and G010214N), the European Research Council (ERC Starting Grant 335476), the University of Sao Paulo-Brazil (USP) and the Foundation for Research Support of the State of Sao Paulo (FAPESP SPEC grant 2013/50420-6)

Adsorptive Separations on Metal-Organic Frameworks

Metal-organic frameworks are a class of microporous materials with exceptionally high pore volumes. Their composition of metal ions and organic linkers creates a chemically diverse environment allowing various potential interactions with adsorbing molecules. Much research has been performed on this class of materials concerning catalysis and gas phase adsorption. The storage of hydrogen gas in metal-organic frameworks is one of the key research topics concerning MOFs. Recently, liquid phase adsorption and separation on MOFs gained interest, although not many data are available yet. This thesis will focus on various separation and purification problems. The separation of a steam cracker s C5-cut will be discussed first using a combination of MOFs and zeolites. MIL-96, an Al-trimesate, is able to separate di-olefins from the other fractions due to sterical and possibly entropical reasons, while [Cu3(BTC)2] can separate olefins from paraffins based on interactions of the olefinic bond with metal sites present in the host material. Using a high silica chabasite zeolite, the separation of linear and branched C5-isomers can be attained due to shape selectivity. A second major separation studied is the separation of ethylbenzene vs styrene and of vinyltoluenes from the corresponding ethyltoluenes. MIL-47, MIL-53 and [Cu3(BTC)2] have been studied and all three materials have similar uptake capacitites and separation factors, but the adsorption in all three materials is based on a different mechanism. The adsorption is entropy driven on MIL-47, while it is enthalpy driven on the analogous structure of MIL-53. On [Cu3(BTC)2], the interaction with the free metal sites as well as the number of p-electrons in the adsorbate seem to be playing an important role. Apart from separations, purification is another important application of liquid phase adsorption. The removal of phenolic compounds from wastewater is an example of this and it is shown that a water stable MOF like MIL-53(Cr) can perform this purification. Due to its organic composition, MIL-53(Cr) is capable of interacting with phenolic compounds and as water is coadsorbed, the regeneration of this material is more straightforward than with classical activated carbon. Finally, the removal of heterocyclic aromatic contaminants from fuel feeds is discussed for a variety of MOFs. It turns out that the Lewis acidity of the free metal sites of a MOF is of crucial importance to adsorb either both sulfur and nitrogen containing contaminants or only nitrogen containing contaminants, underlining the enormous potential that MOFs have for adsorptive applications.status: publishe

Learning exploration/exploitation strategies for single trajectory reinforcement learning

peer reviewedWe consider the problem of learning high-performance Exploration/Exploitation (E/E) strategies for finite Markov Decision Processes (MDPs) when the MDP to be controlled is supposed to be drawn from a known probability distribution pM( ). The performance criterion is the sum of discounted rewards collected by the E/E strategy over an in finite length trajectory. We propose an approach for solving this problem that works by considering a rich set of candidate E/E strategies and by looking for the one that gives the best average performances on MDPs drawn according to pM( ). As candidate E/E strategies, we consider index-based strategies parametrized by small formulas combining variables that include the estimated reward function, the number of times each transition has occurred and the optimal value functions V and Q of the estimated MDP (obtained through value iteration). The search for the best formula is formalized as a multi-armed bandit problem, each arm being associated with a formula. We experimentally compare the performances of the approach with R-max as well as with e-Greedy strategies and the results are promising

Selective adsorption and separation of aromatics with the metal-organic frameworks MIL-47 and MIL-53

status: publishe

Metal-organic frameworks as high-potential adsorbents for liquid-phase separations of olefins, alkylnaphthalenes and dichlorobenzenes

Three metal-organic frameworks (MOFs) with similar pore window diameters, [Cu3(BTC)2], MIL-47 and MIL-53(Al), are tested for adsorption of olefins, alkylnaphthalenes and dichlorobenzenes in the liquid phase. Selective adsorption of olefins is possible only on [Cu3(BTC)2] via pi-complexation on its open metal sites. This material shows a remarkable preference for cis-olefins over trans-olefins. All three MOFs have high affinities for alkylnaphthalene and dichlorobenzene isomers. Separation of 1,4-dimethylnaphthalene from other alkylnaphthalene isomers and of p- and m-dichlorobenzene can be carried out on both MIL-47 and MIL-53(Al), as shown with breakthrough experiments. For the alkylnaphthalenes, column experiments at different concentrations point to enthalpic interactions as important factors determining selectivity, and the occurrence of steric effects during the adsorption of 1,4-dimethylnaphthalene shows that its kinetic diameter approaches the pore diameter of the adsorbents. For the dichlorobenzenes, packing effects dominate the adsorption selectivity.status: publishe

Separation of C-5-Hydrocarbons on Microporous Materials: Complementary Performance of MOFs and Zeolites

This work studies the liquid-phase separation of the aliphatic C-5-diolefins, mono-olefins, and paraffins, a typical feed produced by a steam cracker, with a focus on the seldomly studied separation of the C-5-diolefin isomers isoprene, trans-piperylene, and cis-piperylene Three adsorbents are compared the metal-organic framework MIL-96, which is an aluminum 1,3,5-benzenetricarboxylate, and two zeolites with CHA and LTA topology All three materials have spacious cages that are accessible via narrow cage windows with a diameter of less than 0 5 nm The mechanisms determining adsorption selectivities on the various materials are investigated. Within the diolefin fraction, MIL-96 and chabazite preferentially adsorb trans-piperylene from a mixture containing all three C-5-diolefin isomers with high separation factors and a higher capacity compared to the reference zeolite 5A due to a more efficient packing of the trans isomer in the pores Additionally, chabazite is able to separate cis-piperylene and isoprene based on size exclusion of the branched isomer This makes chabazite suitable for separating all three diolefin isomers Its use in separating linear from branched mono-olefins and paraffins is addressed as well Furthermore, MIL-96 is the only material capable of separating all three diolefin isomers from C-5-mono-olefins and paraffins Finally, the MOF [Cu-3(BTC)(2)] (BTC = benzene-1,3,5-tricarboxylate) is shown to be able to separate C-5-olefins from paraffins On the basis of these observations, a flow scheme can be devised in which the C-5-fraction can be completely separated using a combination of MOFs and zeolitesstatus: publishe

Motion and deformation estimation of cardiac ultrasound sequences using an anatomical B-spline transformation model

We present a novel method for tracking myocardial motion in 2D ultrasound sequences based on non-rigid registration using an anatomical free-form deformation (AFFD) model where the basis functions are locally oriented along the radial and circumferential direction of the left ventricle (LV). This formulation allows us to model the LV motion more naturally compared to previously proposed FFD's defined on a regular Cartesian grid (CFFD). In this paper we compare the performance of the AFFD against the CFFD model in an in-vivo setting. Short-axis images were acquired in five open-chest sheep using sonomicrometry as ground-truth deformation estimates. We demonstrated that regional end-systolic strain values assessed with the AFFD model are comparable with CFFD, while also displaying a statistically lower drift at the end of the cardiac cycle and a better agreement with a manual end-systolic reference. Furthermore, tracking using AFFD was visually more appealing to clinical experts

Pannexin1 as mediator of inflammation and cell death

Pannexins form channels at the plasma membrane surface that establish a pathway for communication between the cytosol of individual cells and their extracellular environment. By doing so, pannexin signaling dictates several physiological functions, but equally underlies a number of pathological processes. Indeed, pannexin channels drive inflammation by assisting in the activation of inflammasomes, the release of pro-inflammatory cytokines, and the activation and migration of leukocytes. Furthermore, these cellular pores facilitate cell death, including apoptosis, pyroptosis and autophagy. The present paper reviews the roles of pannexin channels in inflammation and cell death. In a first part, a state-of-the-art overview of pannexin channel structure, regulation and function is provided. In a second part, the mechanisms behind their involvement in inflammation and cell death are discussed