Killing Me Softly—Future Challenges in Apoptosis Research

The induction of apoptosis, a highly regulated and clearly defined mode of cell dying, is a vital tenet of modern cancer therapy. In this review we focus on three aspects of apoptosis research which we believe are the most crucial and most exciting areas currently investigated and that will need to be better understood in order to enhance the efficacy of therapeutic measures. First, we discuss which target to select for cancer therapy and argue that not the cancer cell as such, but its interaction with the microenvironment is a more promising and genetically stable site of attack. Second, the complexity of combination therapy is elucidated using the PI3-K-mediated signaling network as a specific example. Here we show that the current clinical approach to sensitize malignancies to apoptosis by maximal, prolonged inhibition of so-called survival pathways can actually be counter productive. Third, we propose that under certain conditions which will need to be clearly defined in future, chronification of a tumor might be preferable to the attempt at a cure. Finally, we discuss further problems with utilizing apoptosis induction in cancer therapy and propose a novel potential therapeutic approach that combines the previously discussed features.     

Structure‐Based Mechanism of Oleate Hydratase from Elizabethkingia meningoseptica

Hydratases provide access to secondary and tertiary alcohols by regio‐ and/or stereospecifically adding water to carbon‐carbon double bonds. Thereby, hydroxy groups are introduced without the need for costly cofactor recycling, and that makes this approach highly interesting on an industrial scale. Here we present the first crystal structure of a recombinant oleate hydratase originating from Elizabethkingia meningoseptica in the presence of flavin adenine dinucleotide (FAD). A structure‐based mutagenesis study targeting active site residues identified E122 and Y241 as crucial for the activation of a water molecule and for protonation of the double bond, respectively. Moreover, we also observed that two‐electron reduction of FAD results in a sevenfold increase in the substrate hydration rate. We propose the first reaction mechanism for this enzyme class that explains the requirement for the flavin cofactor and the involvement of conserved amino acid residues in this regio‐ and stereoselective hydration.     

Polyphenolrückgewinnung aus Olivenölabwasser durch Einsatz von Membrantechnologie

Olive mill wastewater (OMW) is obtained as byproduct of oil production in large quantities after the olive harvest, mainly in the Mediterranean region. One problem is the high load of organic matter, such as phytotoxic polyphenols, which causes significant environmental problems. However, due to their antioxidant properties the use of these polyphenols is also popular in several industry branches, e.g. production of plastics, cosmetics and drugs. A combined wastewater treatment permits besides water purification also recovery of the polyphenolic compounds for industrial use. One possibility is membrane technology. An overview of research studies concerning polyphenol recovery from OMW using membrane technologies is given.     

Quantification of non-isothermal,multi-phase crystallization of isotactic polypropylene: The influence of cooling rate and pressure

The structure of semi-crystalline polymers is strongly influenced by the conditions applied during processing and is of major importance for the final properties of the product. A method is presented to quantify the effect of thermal and pressure history on the isotropic and quiescent crystallization kinetics of four important structures of polypropylene, i.e. the α-, β-, γ- and mesomorphic phase. The approach is based on nucleation and growth of spherulites during non-isothermal solidification, described by the Schneider rate equations combined with the Komogoroff-Avrami expression for space filling. Using an optimization routine the time-resolved multi-phase structure development is accurately described using crystal phase dependent growth rates and an overall nucleation density, all as function of temperature and pressure. It is shown that the maximum growth rate of the α-, and γ-phase increases with applied pressure, while it decreases for the mesomorphic phase. Addition of β-nucleation agent is interpreted as a secondary nucleation density with a coupled β-phase growth. This complete crystallization kinetics characterization of isotactic polypropylene allows prediction of the multi-phase structure development for a wide range of quiescent processing conditions.     

Synthesis,morphology and properties of segmented poly(ether ester amide)s comprising uniform glycine or β-alanine extended bisoxalamide hard segments

Segmented poly(ether ester amide)s comprising glycine or β-alanine extended bisoxalamide hard segments are highly phase separated thermoplastic elastomers with a broad temperature independent rubber plateau. These materials with molecular weights, M_n, exceeding 30 × 10³ g mol^?1 are conveniently prepared by polycondensation of preformed bisester–bisoxalamides and commercially available PTHF diols. FT-IR revealed strongly hydrogen bonded and highly ordered bisoxalamide hard segments with degrees of ordering between 73 and 99%. The morphology consists of fiber-like nano-crystals randomly dispersed in the soft polymer matrix. The micro-structural parameters of the copolymers were addressed by simultaneous small- and wide-angle X-ray scattering. It is shown that the crystals have strictly identical thickness, which is close to the contour length of the hard segment. The long dimension of the crystals is identified with the direction of the hydrogen bonds. The melting transitions of the hard segments are sharp, with temperatures up to 170 °C. The studied polymers have an elastic modulus in the range of 139–170 MPa, a stress at break in the range of 19–31 MPa combined with strains at break of higher than 800%. The segmented copolymer comprising the β-alanine based bisoxalamide hard segment with a spacer of 6 methylene groups has a melting transition of 141 °C which is higher than the melting transition of its glycine analogue of 119 °C. Likewise, the fracture stress increased from 22 to 31 MPa when the glycine ester group in the hard segment was replaced with β-alanine. The improved thermal and mechanical properties of the latter polymers is related to the crystal packing of the β-alanine based hard segments in the copolymer compared to the packing of the hard segments comprising glycine ester groups.     

Chemical-Shift Perturbations Reflect Bile Acid Binding to Norovirus Coat Protein: Recognition Comes in Different Flavors

Bile acids have been reported as important cofactors promoting human and murine norovirus (NoV) infections in cell culture. The underlying mechanisms are not resolved. Through the use of chemical shift perturbation (CSP) NMR experiments, we identified a low-affinity bile acid binding site of a human GII.4 NoV strain. Long-timescale MD simulations reveal the formation of a ligand-accessible binding pocket of flexible shape, allowing the formation of stable viral coat protein–bile acid complexes in agreement with experimental CSP data. CSP NMR experiments also show that this mode of bile acid binding has a minor influence on the binding of histo-blood group antigens and vice versa. STD NMR experiments probing the binding of bile acids to virus-like particles of seven different strains suggest that low-affinity bile acid binding is a common feature of human NoV and should therefore be important for understanding the role of bile acids as cofactors in NoV infection.     

Mammalian-Like Inflammatory and Pro-Resolving Oxylipins in Marine Algae

Oxylipins constitute a family of oxidized fatty acids, that are well known as tissue hormones in mammals. They contribute to inflammation and its resolution. The major classes of these lipid mediators are inflammatory prostaglandins (PGs) and leukotrienes (LTs) as well as pro-resolving resolvins (Rvs). Understanding their biosynthetic pathways and modes of action is important for anti-inflammatory interventions. Besides mammals, marine algae also biosynthesize mammalian-like oxylipins and thus offer new opportunities for oxylipin research. They provide prolific sources for these compounds and offer unique opportunities to study alternative biosynthetic pathways to the well-known lipid mediators. Herein, we discuss recent findings on the biosynthesis of oxylipins in mammals and algae including an alternative pathway to prostaglandin E₂, a novel pathway to a precursor of leukotriene B₄, and the production of resolvins in algae. We evaluate the pharmacological potential of the algal metabolites with implications in health and disease.