A high-throughput metabolomics method to predict high concentration cytotoxicity of drugs from low concentration profiles

A major source of drug attrition in pharmacological development is drug toxicity, which eventually manifests itself in detrimental physiological effects. These effects can be assessed in large sample cohorts, but generating rich sets of output variables that are necessary to predict toxicity from lower drug dosages is problematic. Currently the throughput of methods that enable multi-parametric cellular readouts over many drugs and large ranges of concentrations is limited. Since metabolism is at the core of drug toxicity, we develop here a high-throughput intracellular metabolomics platform for relative measurement of 50-100 targeted metabolites by flow injection-tandem mass spectrometry. Specifically we focused on central metabolism of the yeast Saccharomyces cerevisiae because potential cytotoxic effects of drugs can be expected to affect this ubiquitous core network. By machine learning based on intracellular metabolite responses to 41 drugs that were administered at seven concentrations over three orders of magnitude, we demonstrate prediction of cytotoxicity in yeast from intracellular metabolome patterns obtained at much lower drug concentrations that exert no physiological toxicity. Furthermore, the 13C-determined intracellular response of metabolic fluxes to drug treatment demonstrates the functional performance of the network to be rather robust, until growth was compromised. Thus we provide evidence that phenotypic robustness to drug challenges is achieved by a flexible make-up of the metabolom

The price of informality : how informal finance schemes defaulted in China, 1989–2015.

The default of a large number of informal finance schemes in China has caused enormous financial losses, and therefore has potential social and political significance. Analysing 354 defaulted schemes from 1989 to 2015, this study defines how they differ from other types of informal finance. It also produces an ideal-type representation of the default process and concludes that the default results from greed, increasing financial pressure at the individual level and private enterprises’ restricted access to state bank loans at the institutional level. China’s financial system should be more flexible in order to prevent further financial losses through informal financial relations

Straightforward determination of the degree of N-acetylation of chitosan by means of first-derivative UV spectrophotometry

First-derivative UV spectrophotometry is shown to be a reliable method for the determination of the degree of N-acetylation of chitosan samples. A mathematical expression is derived that allows to determine the DA directly from the mass concentration of a chitosan solution and the first derivative of its UV spectrum at 202 nm, thus eliminating the need for empiric correction curves for highly deacetylated samples. A procedure is proposed for the accurate mass determination of the hygroscopic chitosan. The proposed approach facilitates the routine determination of the DA, especially when using potent multiwell microplate readers, which allow hundreds of samples to be measured in just a few minutes

Current state and challenges for dynamic metabolic modeling

While the stoichiometry of metabolism is probably the best studied cellular level, the dynamics in metabolism can still not be well described, predicted and, thus, engineered. Unknowns in the metabolic flux behavior arise from kinetic interactions, especially allosteric control mechanisms. While the stoichiometry of enzymes is preserved in vitro, their activity and kinetic behavior differs from the in vivo situation. Next to this challenge, it is infeasible to test the interaction of each enzyme with each intracellular metabolite in vitro exhaustively. As a consequence, the whole interacting metabolome has to be studied in vivo to identify the relevant enzymes properties. In this review we discuss current approaches for in vivo perturbation experiments, that is, stimulus response experiments using different setups and quantitative analytical approaches, including dynamic carbon tracing. Next to reliable and informative data, advanced modeling approaches and computational tools are required to identify kinetic mechanisms and their parameters.The authors EV, AT, KN, IR, MO, DM and AW are part of the ERA-IB funded consortium DYNAMICS (ERA-IB-14-081, NWO 053.80.724)

Collective memory and autobiographical memory: Perspectives from the humanities and cognitive sciences

The current overview provides an interdisciplinary synthesis of autobiographical and collective memory studies, focusing on history and cognitive psychology, to help other scholars bridge the disciplinary gap. We describe the various interpretative frameworks used to build theoretical knowledge on how autobiographical memory and collective memory are intertwined. We expose how research exploring self, social and directive functions of autobiographical memory echoes three main functions that can be identified for collective memory, that is, social identity, social schemata, and means for actions, or a political decision tool of research in these fields. In doing so, we hope to stimulate opportunities for more interdisciplinary research. This article is categorized under: Psychology > Memory Psychology > Theory and Method

Macro and nano dimensional plant fiber reinforcements for Cementitious Composites

uncorrected proofNowadays, the use of plant fibers in the civil construction industry is growing rapidly due to their low cost, light weight and good specific mechanical properties, lower health hazard, and environmental benefits. Nanodimensional fibers derived from plants such as nanocellulose are also getting considerable attention due to their excellent mechanical properties. This chapter discusses these different types of plant fibers and their derivatives which have huge application potential in the civil construction sector. The influence of plant fibers on microstructure as well as on physical–mechanical properties of cementitious composites are discussed in detail. The challenges regarding plant fiber processing and dispersion, the fiber/matrix interface, and the durability of plant fiber-cement composites are also addressed. The application of nanocellulose in polymer composites has been included in this chapter just to provide the readers sufficient background information and techniques to inspire engineered cement-based composites. Finally, the chapter concludes with the current application of plant fibers in civil construction and the future trends(undefined)info:eu-repo/semantics/publishedVersio

Design of eco-friendly fabric softeners: structure, rheology and interaction with cellulose nanocrystals

Concentrated fabric softeners are water-based formulations containing around 10 - 15 wt. % of double tailed esterquat surfactants primarily synthesized from palm oil. In recent patents, it was shown that a significant part of the surfactant contained in today formulations can be reduced by circa 50 % and replaced by natural guar polymers without detrimental effects on the deposition and softening performances. We presently study the structure and rheology of these softener formulations and identify the mechanisms at the origin of these effects. The polymer additives used are guar gum polysaccharides, one cationic and one modified through addition of hydroxypropyl groups. Formulations with and without guar polymers are investigated using optical and cryo-transmission electron microscopy, small-angle light and Xray scattering and finally rheology. Similar techniques are applied to study the phase behavior of softener and cellulose nanocrystals considered here as a model for cotton. The esterquat surfactants are shown to assemble into micron-sized vesicles in the dilute and concentrated regimes. In the former, guar addition in small amounts does not impair the vesicular structure and stability. In the concentrated regime, cationic guars induce a local crowding associated to depletion interactions and leads to the formation of a local lamellar order. In rheology, adjusting the polymer concentration at one tenth that of the surfactant is sufficient to offset the decrease of the elastic property associated with the surfactant reduction. In conclusion, we have shown that through an appropriate choice of natural additives it is possible to lower the concentration of surfactants in fabric conditioners by about half, a result that could represent a significant breakthrough in current home care formulations.Comment: 10 pages 8 figure

Traditional Cultural Artmaking Practices and Their Impact on Wellness

This study explores the impact that traditional artmaking can have on the wellness of individuals who continue to practice their traditional crafts. Limited research has explored how culturally adapted art therapy practices and culturally relevant materials can promote wellness and alleviate emotional and acculturation challenges for multicultural populations. This research included a case study approach that invited five participants who regularly engaged in a traditional artmaking practice to continue their practice for four consecutive weeks and reflect on their sense of wellness after each traditional artmaking engagement. Over the four weeks, participants completed an initial survey to assess their baseline sense of wellness, weekly surveys that included the WHO-5 Well-being Index, and a final interview over Zoom web conferencing. Through a thematic analysis of the qualitative data, the researchers recognized two overarching themes: (1) the sense of wellness through experiencing a connection to culture, and (2) connection to heritage and present-moment awareness. The survey results revealed that environmental stressors often impacted the participant’s ability to rate wellness in connection to their artmaking practice and that their practice was a helpful distraction that positively impacted wellness. This research suggests that engaging in traditional cultural art practices can increase an individual’s sense of wellness through a deeper connection to their culture and their present-moment awareness. Further studies regarding traditional cultural artmaking practices and their impact on wellness may inspire and support art therapists in decolonizing therapeutic approaches and empowering multicultural communities and individuals

Optical Sectioning for Reflection Interference Microscopy: Quantitative Imaging at Soft Interfaces

Reflection interference contrast microscopy (RICM, also known as interference reflection microscopy) and related techniques have become of wide interest to the biophysical, soft matter, and biochemistry communities owing to their exquisite sensitivity for characterizing thin films or individual nanoscopic objects adsorbed onto surfaces, or for monitoring cell-substrate interactions. Over the recent years, striking progress has been made to improve the sensitivity and the quantitative analysis of RICM. Its use in more complex environments, with spurious reflections stemming from a variety of structures in the sample, remains however challenging. In this paper, we demonstrate two optical sectioning methods that effectively reduce such background and can be readily implemented in a conventional RICM setup: line confocal detection and structured illumination microscopy. We characterize experimentally the benefits to image quality and demonstrate the use of the methods for quantitative imaging of complex biological and biomimetic samples: cellular membranes, thin organic films, biofunctional surfaces. We then discuss the benefits of each method and provide guidelines to arbitrate between sectioning and signal-to-noise ratio. Finally, we provide a detailed description of our experimental setup and a home-written image acquisition and processing software that should allow the interested reader to duplicate such a setup on a home-built or commercial microscope

Aphanomyces euteiches Cell Wall Fractions Containing Novel Glucan-Chitosaccharides Induce Defense Genes and Nuclear Calcium Oscillations in the Plant Host Medicago truncatula

[EN] N-acetylglucosamine-based saccharides (chitosaccharides) are components of microbial cell walls and act as molecular signals during host-microbe interactions. In the legume plant Medicago truncatula, the perception of lipochitooligosaccharide signals produced by symbiotic rhizobia and arbuscular mycorrhizal fungi involves the Nod Factor Perception (NFP) lysin motif receptor-like protein and leads to the activation of the so-called common symbiotic pathway. In rice and Arabidopsis, lysin motif receptors are involved in the perception of chitooligosaccharides released by pathogenic fungi, resulting in the activation of plant immunity. Here we report the structural characterization of atypical chitosaccharides from the oomycete pathogen Aphanomyces euteiches, and their biological activity on the host Medicago truncatula. Using a combination of biochemical and biophysical approaches, we show that these chitosaccharides are linked to β-1,6-glucans, and contain a β-(1,3;1,4)-glucan backbone whose β-1,3-linked glucose units are substituted on their C-6 carbon by either glucose or N-acetylglucosamine residues. This is the first description of this type of structural motif in eukaryotic cell walls. Glucan-chitosaccharide fractions of A. euteiches induced the expression of defense marker genes in Medicago truncatula seedlings independently from the presence of a functional Nod Factor Perception protein. Furthermore, one of the glucan-chitosaccharide fractions elicited calcium oscillations in the nucleus of root cells. In contrast to the asymmetric oscillatory calcium spiking induced by symbiotic lipochitooligosaccharides, this response depends neither on the Nod Factor Perception protein nor on the common symbiotic pathway. These findings open new perspectives in oomycete cell wall biology and elicitor recognition and signaling in legumes.SIThis work is part of the “Laboratoire d’Excellence” (LABEX) entitled TULIP (ANR -10-LABX-41); it was funded by the Région Midi-Pyrénées, the CNRS (PhD grant INEE 36 to AN), and the French Agence Nationale de la Recherche (ANR-08-BLAN-0208-01 “Sympasignal”)