Well dispersed fractal aggregates as filler in polymer-silica nanocomposites: long range effects in rheology

We are presenting a new method of processing polystyrene-silica nanocomposites, which results in a very well-defined dispersion of small primary aggregates (assembly of 15 nanoparticles of 10 nm diameter) in the matrix. The process is based on a high boiling point solvent, in which the nanoparticles are well dispersed, and controlled evaporation. The filler's fine network structure is determined over a wide range of sizes, using a combination of Small Angle Neutron Scattering (SANS) and Transmission Electronic Microscopy (TEM). The mechanical response of the nanocomposite material is investigated both for small (ARES oscillatory shear and Dynamical Mechanical Analysis) and large deformations (uniaxial traction), as a function of the concentration of the particles. We can investigate the structure-property correlations for the two main reinforcement effects: the filler network contribution, and a filler-polymer matrix effect. Above a silica volume fraction threshold, we see a divergence of the modulus correlated to the build up of a connected network. Below the threshold, we obtain a new additional elastic contribution of much longer terminal time than the matrix. Since aggregates are separated by at least 60 nm, this new filler-matrix contribution cannot be described solely with the concept of glassy layer (2nm)

The Proteome of BLOC-1 Genetic Defects Identifies the Arp2/3 Actin Polymerization Complex to Function Downstream of the Schizophrenia Susceptibility Factor Dysbindin at the Synapse

Proteome modifications downstream of monogenic or polygenic disorders have the potential to uncover novel molecular mechanisms participating in pathogenesis and/or extragenic modification of phenotypic expression. We tested this idea by determining the proteome sensitive to genetic defects in a locus encoding dysbindin, a protein required for synapse biology and implicated in schizophrenia risk. We applied quantitative mass spectrometry to identify proteins expressed in neuronal cells the abundance of which was altered after downregulation of the schizophrenia susceptibility factor dysbindin (Bloc1s8) or two other dysbindin-interacting polypeptides, which assemble into the octameric biogenesis of lysosome-related organelles complex 1 (BLOC-1). We found 491 proteins sensitive to dysbindin and BLOC-1 loss of function. Gene ontology of these 491 proteins singled out the actin cytoskeleton and the actin polymerization factor, the Arp2/3 complex, as top statistical molecular pathways contained within the BLOC-1-sensitive proteome. Subunits of the Arp2/3 complex were downregulated by BLOC-1 loss of function, thus affecting actin dynamics in early endosomes of BLOC-1-deficient cells. Furthermore, we demonstrated that Arp2/3, dysbindin, and subunits of the BLOC-1 complex biochemically and genetically interact, modulating Drosophila melanogaster synapse morphology and homeostatic synaptic plasticity. Our results indicate that ontologically prioritized proteomics identifies novel pathways that modify synaptic phenotypes associated with neurodevelopmental disorder gene defects

Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(−) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(−) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(−) cases are required to understand this important LUAD subset. © 2021 The AuthorsCarrot-Zhang et al. perform whole-genome characterization of lung adenocarcinomas (LUADs) lacking RTK/RAS/RAF pathway alterations (RPAs) and identify mutations or structural variants in both coding and non-coding spaces that define a unique entity of RPA(−) LUADs and potentially explain the underlying biology of this disease

Integrating precision cancer medicine into healthcare—policy, practice, and research challenges

Abstract Precision medicine (PM) can be defined as a predictive, preventive, personalized, and participatory healthcare service delivery model. Recent developments in molecular biology and information technology make PM a reality today through the use of massive amounts of genetic, ‘omics’, clinical, environmental, and lifestyle data. With cancer being one of the most prominent public health threats in developed countries, both the research community and governments have been investing significant time, money, and efforts in precision cancer medicine (PCM). Although PCM research is extremely promising, a number of hurdles still remain on the road to an optimal integration of standardized and evidence-based use of PCM in healthcare systems. Indeed, PCM raises a number of technical, organizational, ethical, legal, social, and economic challenges that have to be taken into account in the development of an appropriate health policy framework. Here, we highlight some of the more salient issues regarding the standards needed for integration of PCM into healthcare systems, and we identify fields where more research is needed before policy can be implemented. Key challenges include, but are not limited to, the creation of new standards for the collection, analysis, and sharing of samples and data from cancer patients, and the creation of new clinical trial designs with renewed endpoints. We believe that these issues need to be addressed as a matter of priority by public health policymakers in the coming years for a better integration of PCM into healthcare

Erratum to ‘Dissolution of LnYSiAlO glass (Ln=La or Ce) in aqueous media. I. Influence of the pH on hydrolysis mechanisms and kinetics'

AC

Polymer-Grafted Silicon Nanoparticles Obtained Either via Peptide Bonding or Click Chemistry

International audiencePegylated silicon nanoparticles (SiNPs) are of great interest for applications in bio-imaging as fluorescent tracers. Poly(ethylene glycol) (PEG) covalently attached to SiNPs may improve the (bio)compatibility, solubility in water and stability of SiNPs, without inhibiting their optical properties. SiNPs are first coated with silica followed by a silanization of the surface. Then, two versatile "grafting to" methods are used to provide pegylated SiNPs. Both peptide type coupling and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) are conducted and compared to graft PEG of different chain lengths. Infra-red spectroscopy, thermogravimetric analysis and transmission electron microscopy prove that theses methodologies are simple and efficient for the preparation of functional inorganic nanoparticles with luminescent properties

Water-Soluble Polymer-Grafted Platinum Nanoparticles for the Subsequent Binding of Enzymes. Synthesis and SANS

International audienceFunctionalized platinum nanoparticles (PtNPs) possess catalytic properties towards H202 oxidation, which are of great interest for the elaboration of electrochemical biosensors. To improve the understanding of phenomena involved in such systems, we designed platinum-polymer-enzyme model nanostructures according to a bottom-up approach. These structures have been elaborated from elementary building units based on polymer-grafted PtNPs obtained from surface initiated-atom transfer radical polymerization. This paper describes the polymerization of ter-butyl methacrylate from PtNPs and its subsequent hydrolysis to obtain a water-soluble corona, followed by an activated ester modification to introduce an enzyme (glucose oxidase). The structure of the objects, the molecular weight and the grafting density of the polymer chains were principally elucidated by small angle neutron scattering (SANS). After the grafting of the enzyme, the final hybrid structures were characterized by both microscopy and SANS to attest for the covalent grafting of the enzyme. Composition and enzyme activity of the nanohybrid objects, have also been determined by UV spectroscopy