Subunit Interactions and cooperativity in the microtubule-severing AAA ATPase spastin

Spastin is a hexameric ring AAA ATPase that severs microtubules. To see whether the ring complex funnels the energy of multiple ATP hydrolysis events to the site of mechanical action, we investigate here the cooperativity of spastin. Several lines of evidence indicate that interactions among two subunits dominate the cooperative behavior: (i) the ATPase activity shows a sigmoidal dependence on the ATP concentration; (ii) ATPγS displays a mixed-inhibition behavior for normal ATP turnover; and (iii) inactive mutant subunits inhibit the activity of spastin in a hyperbolic dependence, characteristic for two interacting species. A quantitative model based on neighbor interactions fits mutant titration experiments well, suggesting that each subunit is mainly influenced by one of its neighbors. These observations are relevant for patients suffering from SPG4-type hereditary spastic paraplegia and explain why single amino acid exchanges lead to a dominant negative phenotype. In severing assays, wild type spastin is even more sensitive toward the presence of inactive mutants than in enzymatic assays, suggesting a weak coupling of ATPase and severing activity.     

Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series

Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.     

Α-amino-β-fluorocyclopropanecarboxylic acids as a new tool for drug development: synthesis of glutamic acid analogs and agonist activity towards metabotropic glutamate receptor 4

Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340 nM.     

Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains

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Single-Cell Analysis Reveals Heterogeneity of High Endothelial Venules and Different Regulation of Genes Controlling Lymphocyte Entry to Lymph Nodes

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Efficiencies of selected biotreatments for the remediation of PAH in diluted bitumen contaminated soil microcosms

Unconventional oils such as diluted bitumen from oil sands differs from most of conventional oils in terms of physiochemical properties and PAHs composition. This raises concerns regarding the effectiveness of current remediation strategies and protocols originally developed for conventional oil. Here we evaluated the efficiency of different biotreatment approaches, such as fungi inoculation (bioaugmentation), sludge addition (bioaugmentation/biostimulation), perennial grasses plantation (phytoremediation) and their combinations as well as natural attenuation (as control condition), for the remediation of soil contaminated by synthetic crude oil (a product of diluted bitumen) in laboratory microcosms. We specifically monitored the PAHs loss percentage (alkylated PAHs and unsubstituted 16 EPA Priority PAHs), the residue of PAHs and evaluated the ecotoxicity of soil after treatment. All treatments were highly efficient with more than?~?80% of ∑PAHs loss after 60 days. Distinctive loss efficiencies between light PAHs (≤?3 rings,?~?96% average loss) and heavy PAHs (4–6 rings,?~?29% average loss) were observed. The lowest average PAHs residue (0.10?±?0.02 mg·kg^?1, for an initial concentration of 0.29?±?0.12 mg·kg^?1) was achieved with the “sludge—plants (grasses)” combination. Sludge addition was the only treatment that achieved significantly lower ecotoxicity (3%?±?4% of growth inhibition of L. sativa) than the control (natural attenuation, 13%?±?4% of inhibition). Sludge addition, grasses plantation and “sludge—fungi combination” treatments could result in lower PAH exposure (than other treatments) in post-treated soil when using the Canadian Soil Quality Guidelines for the protection of environmental and human health for potentially carcinogenic and other PAHs.

     

How to take time into account in the inventory step: a selective introduction based on sensitivity analysis

Purpose

Life cycle assessment is usually an assessment tool, which only considers steady-state processes, as the temporal and spatial dimensions are lost during the life cycle inventory (LCI). This approach therefore reduces the environmental relevance of certain results, as it has been underlined in the case of climate change studies. Given that the development of dynamic impact methods is based on dynamic inventory data, it seems essential to develop a general methodology to achieve a temporal LCI.

Methods

This study presents a method for selecting the steps, within the whole process network, for which dynamics need to be considered while others can be approximated by steady-state representation. The selection procedure is based on the sensitivity of the impacts on the variation of environmental and economic flows. Once these flows have been identified, their respective timescales are compared to the inherent timescales of the impact categories affected by the flows. The timescales of the impacts are divided into three categories (days, months, years) based on a literature review of the ReCiPe method. The introduction of a temporal dynamic depends on the relationship between the timescale of the environmental and economic flows on the one hand and that of the concerned impact on the other hand.

Results and discussion

This approach is illustrated by the life cycle assessment of palm methyl ester and ethanol from sugarcane. In both cases, the introduction of a temporal dynamic is limited to a small proportion of the total number of flows: 0.1 % in the sugarcane ethanol production and 0.01 % in the palm methyl ester production. Future developments of time integration in the LCI and in the life cycle impact assessment (LCIA) are also discussed in order to deal with the need of characterization functions and the recurrent problem of waiting times.

Conclusions

This work provides a method to select specific flows where the introduction of temporal dynamics is most relevant. It is based on sensitivity analyses and on the relationship between the timescales of the flows and the timescale of the involved impact. The time-distributed LCI generated by using this approach could then be coupled with a dynamic LCIA proposed in the literature.     

Functional normalization of 450k methylation array data improves replication in large cancer studies

We propose an extension to quantile normalization that removes unwanted technical variation using control probes. We adapt our algorithm, functional normalization, to the Illumina 450k methylation array and address the open problem of normalizing methylation data with global epigenetic changes, such as human cancers. Using data sets from The Cancer Genome Atlas and a large case–control study, we show that our algorithm outperforms all existing normalization methods with respect to replication of results between experiments, and yields robust results even in the presence of batch effects. Functional normalization can be applied to any microarray platform, provided suitable control probes are available.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-014-0503-2) contains supplementary material, which is available to authorized users.