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Aiming to enhance the analysis of water consumption and resulting consequences along the supply chain of products, the water accounting and vulnerability evaluation (WAVE) model is introduced. On the accounting level, atmospheric evaporation recycling within drainage basins is considered for the first time, which can reduce water consumption volumes by up to 32%. Rather than predicting impacts, WAVE analyzes the vulnerability of basins to freshwater depletion. Based on local blue water scarcity, the water depletion index (WDI) denotes the risk that water consumption can lead to depletion of freshwater resources. Water scarcity is determined by relating annual water consumption to availability in more than 11?000 basins. Additionally, WDI accounts for the presence of lakes and aquifers which have been neglected in water scarcity assessments so far. By setting WDI to the highest value in (semi)arid basins, absolute freshwater shortage is taken into account in addition to relative scarcity. This avoids mathematical artifacts of previous indicators which turn zero in deserts if consumption is zero. As illustrated in a case study of biofuels, WAVE can help to interpret volumetric water footprint figures and, thus, promotes a sustainable use of global freshwater resources. [ABSTRACT FROM AUTHOR]

Due to global increase of freshwater scarcity, knowledge about water consumption in product life cycles is important This study analyzes water consumption and the resulting impacts of Volkswagen's car models Polo, Golf and Passat and represents the first application of impact-oriented water footprint methods on complex industrial products. Freshwater consumption throughout the cars' life cycles is allocated to material groups and assigned to countries according to import mix shares or location of production sites. Based on these regionalized water inventories, consequences for human health, ecosystems, and resources are determined by using recently developed impact assessment methods. Water consumption along the life cycles of the three cars ranges from 52 to 83 m3/car, of which more than 95% is consumed in the production phase, mainly resulting from producing iron, steel, precious metals, and polymers. Results show that water consumption takes place in 43 countries worldwide and that only 10% is consumed directly at Volkswagen's production sites. Although impacts on health tend to be dominated by water consumption in South Africa and Mozambique, resulting from the production of precious metals and aluminum, consequences for ecosystems and resources are mainly caused by water consumption of material production in Europe. [ABSTRACT FROM AUTHOR]

ABSTRACT: Saturation transfer difference (STD) NMR experiments on human N-acetylglucosamine kinase (GlcNAc kinase) have been used to determine binding epitopes for the G1cNAc and ATP substrates and their analogues. The study reveals that during the enzyme reaction the binding mode of both substrates is conserved, although the binding affinity of the sugar is reduced. This suggests that the protein does not undergo any significant structural changes during catalysis. Our experiments also demonstrate that G1cNAc kinase has residual activity in the absence of Mg2+. Furthermore, our experiments clearly show that the GlcNAc kinase predominately, if not exclusively, produces the α anomer of phosphorylated sugars. To identify the minimum requirements for substrate binding, a detailed analysis of different natural occurring as well as synthetic sugars was employed. Modifications at the 1, 2, 3, 4 and 6 position as well as the N-acetyl group greatly reduce the binding affinity. In addition, the binding mode of these substrate analogues is often also changed. The high β anomeric preference of G1cNAc kinase along with the drastically reduced binding affinity for sugars other than G1cNAc, suggests that GlcNAc kinase phosphorylates fi-G1cNAc in cells. [ABSTRACT FROM AUTHOR]

The first total synthesis of the boron-containing macrodiolide antibiotic tartrolon B is reported in full detail. Two convergent approaches to the target compound are described, the first of which eventually failed, due to sensitive functionality. In the second, successful route the key step was a stereoselective boron-mediated aldol addition of a bicyclic acetonide protected ketone to a dienealdehyde. In this case the synthesis could be completed without major problems, using a Yamaguchi dimerization macrolactonization endgame. [ABSTRACT FROM AUTHOR]

Examines the stability and selectivity of unnatural DNA with five-membered-ring nucleobase analogues. Effort ot develop orthogonal third base pair for storage in genetic information; Identification of selective against mispairing against with native bases; Use of hydrophobic bases to circumvent hydrogen bonding pattern of natural nase pairs.

Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone. [ABSTRACT FROM AUTHOR]

A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment. [ABSTRACT FROM AUTHOR]

Hereditary inclusion body myopathy (HIBM), a neuromuscular disorder, is caused by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis. To date, more than 40 different mutations in the GNE gene have been reported to cause the disease. Ten of them, representing mutations in both functional domains of GNE, were recombinantly expressed in insect cells (Sf9). Each of the mutants that was analyzed displayed a reduction in the two known GNE activities, thus revealing that mutations may also influence the function of the domain not harboring them. The extent of reduction strongly differs among the point mutants, ranging from only 20% reduction found for A631T and A631V to almost 80% reduction of at least one activity in D378Y and N519S mutants and more than 80% reduction of both activities of G576E, underlined by structural changes of N519S and G576E, as observed in CD spectroscopy and gel filtration analysis, respectively. We therefore generated models of the three-dimensional structures of the epimerase and the kinase domains of GNE, based on Escherichia coli UDP-N-acetylglucosamine 2-epimerase and glucokinase, respectively, and determined the localization of the HIBM mutations within these proteins. Whereas in the kinase domain most of the mutations are localized inside the enzyme, mutations in the epimerase domain are mostly located at the protein surface. Otherwise, the different mutations result in different enzymatic activities but not in different disease phenotypes and, therefore, do not suggest a direct role of the enzymatic function of GNE in the disease mechanism. [ABSTRACT FROM AUTHOR]