Using Life-Cycle Assessment in Process Design

This article presents the application of life-cycle assessment in early phases of process design in the context of technology that employs a bio-based material. The goal is to identify hot spots in the process chains with regard to environmental impacts by performing a dominance analysis. By focusing his activities on the hot spots identified, the designer is given the opportunity to efficiently improve environmental performance. This approach is illustrated for the case of supercritical water gasification, a novel technology for the treatment of organic feedstock with high moisture content. In the reactor under supercritical conditions, organic components are converted into a high-caloric synthesis gas, with hydrogen, methane, and carbon dioxide as the main products. The data used for the assessment are obtained from laboratory tests and the literature, completed by assumptions for missing data. The scope of assessment ranges from the extraction of raw materials to the product, that is, hydrogen (cradle to gate) with sewage sludge of a municipal wastewater treatment plant used as feedstock. The assessment identifies the main sources of environmental impacts. The predominant process step in terms of global warming potential is the supply of the gasification process with additional heat. The production of a blending agent in the dewatering step is the main source of the impact category of acidification, whereas the wastewater treatment plant is the origin of emissions that lead to eutrophication. The revealed sources are analyzed further and options for reducing the environmental impacts are discussed.     

Motor unit discharge rate is correlated within individuals: A case for multilevel model statistical analysis

Statistical analysis of motor unit discharge rate commonly uses the ordinary least squares based ANOVA and regression analyses or a repeated-measures ANOVA is used to account for within motor unit variance when the same motor unit is assessed multiple times. Both of these methods assume statistical independence of multiple motor units assessed within an individual. This investigation details two studies which quantify the statistical dependence of motor units within an individual. During a ramp contraction, motor unit initial discharge rate is mildly correlated within an individual (ICC: 0.11), though accounting for this effect significantly impacts regression analysis (p = 0.01). When a contraction is held at constant force and multiple observations are made on a motor unit, the motor unit discharges are more highly correlated (ICC: 0.41), even after accounting for the effects of multiple motor unit observations. A subject-level ICC of 0.01 can increase Type 1 error rate to 3.9–19.7%, depending on the number of motor units and study subjects. The increase in Type 1 error due to subject-level effects can be mitigated through the use of multilevel modeling techniques. This study details the use and benefit of multilevel models when statistically analyzing motor unit discharge data.     

helixCAM: A platform for programmable cellular assembly in bacteria and human cells

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Significant Discovery of Tetrahydrothieno[3,2‐c]pyridine‐2‐carboxamide Analogs as Potent P2Y12 Receptor Antagonists

A series of analogs containing tetrahydrothieno[3,2‐c]pyridine‐2‐carboxamide as a building block with numerous alicyclic and aromatic amines were synthesized. All analogs were characterized by spectral analysis and evaluated for their in vitro antiplatelet activity. 4‐Fluorophenyl amide derivatives (compounds 8 – 11 ) have been found to be most active in the series with respect to prasugrel and aspirin, a third generation antiplatelet agents (P2Y12 receptor antagonists). Docking study also manifested the admirable binding mode of in vitro active compounds 10 and 11 with the target protein. The results may provide a new perception for future pharmacophore with simple design strategy and avoid tedious synthesis of clopidogrel and prasugrel.     

Characterizing hydration sites in protein-ligand complexes towards the design of novel ligands

Water is an essential part of protein binding sites and mediates interactions to ligands. Its displacement by ligand parts affects the free binding energy of resulting protein-ligand complexes. Therefore the characterization of solvation properties is important for design. Of particular interest is the propensity of localized water to be favorably displaced by a ligand. This review discusses two popular computational approaches addressing these questions, namely WaterMap based on statistical mechanics analysis of MD simulations and 3D RISM based on integral equation theory of liquids. The theoretical background and recent applications in structure-based design will be presented.     

Novel benzotriazole N-acylarylhydrazone hybrids: Design,synthesis, anticancer activity,effects on cell cycle profile,caspase-3 mediated apoptosis and FAK inhibition

A series of novel benzotriazole N-acylarylhydrazone hybrids was synthesized according fragment-based design strategy. All the synthesized compounds were evaluated for their anticancer activity against 60 human tumor cell lines by NCI (USA). Five compounds: 3d, 3e, 3f, 3o and 3q exhibited significant to potent anticancer activity at low concentrations. Compound 3q showed the most prominent broad-spectrum anticancer activity against 34 tumor cell lines, with mean growth inhibition percent of 45.80%. It exerted the highest potency against colon HT-29 cell line, with cell growth inhibition 86.86%. All leukemia cell lines were highly sensitive to compound 3q. Additionally, compound 3q demonstrated lethal activity to MDA-MB-435 belonging melanoma. Compound 3e exhibited the highest anticancer activity against leukemic CCRF-CEM and HL-60(TB) cell lines, with cell growth inhibition 86.69% and 86.42%, respectively. Moreover, it exerted marked potency against ovarian OVCAR-3 cancer cell line, with cell growth inhibition 78.24%. Four compounds: 3d, 3e, 3f and 3q were further studied through determination of IC₅₀ values against the most sensitive cancer cell lines. The four compounds exhibited highly potent anticancer activity against ovarian cancer OVCAR-3 and leukemia HL-60 (TB) cell lines, with IC₅₀ values in nano-molar range between 25 and 130 nM. They showed 18–2.3 folds more potent anticancer activity than doxorubicin. The most prominent compound was 3e, (IC₅₀ values 29 and 25 nM against OVCAR-3 and HL-60 (TB) cell lines, respectively), representing 10 and 18 folds more potency than doxorubicin. The anti-proliferative activity of these four compounds appeared to correlate well with their ability to inhibit FAK at nano-molar range between 44.6 and 80.75 nM. Compound 3e was a potent, inhibitor of FAK and Pyk2 activity with IC₅₀ values of 44.6 and 70.19 nM, respectively. It was 1.6 fold less potent for Pyk2 than FAK. Additionally, it displayed inhibition in cell based assay measuring phosphorylated-FAK (IC₅₀ = 32.72 nM). Inhibition of FAK enzyme led to a significant increase in the level of active caspase-3, compared to control (11.35 folds), accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining in addition to cell cycle arrest at G2/M phase indicating that cell death proceeded through an apoptotic mechanism.     

High‐resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand

The Mapkap kinases 2 and 3 (MK2 and MK3) have been implicated in intracellular signaling pathways leading to the production of the pro‐inflammatory cytokine tumor necrosis factor alpha. MK2 has been pursued by the biopharmaceutical industry for many years for the development of a small molecule anti‐inflammatory treatment and drug‐like inhibitors have been described. The development of some of these compounds, however, has been slowed by the absence of a high‐resolution crystal structure of MK2. Herein we present a high‐resolution (1.9 Å) crystal structure of the highly homologous MK3 in complex with a pharmaceutical lead compound. While all of the canonical features of Ser/Thr kinases in general and MK2 in particular are recapitulated in MK3, the detailed analysis of the binding interaction of the drug‐like ligand within the adenine binding pocket allows relevant conclusions to be drawn for the further design of potent and selective drug candidates.