A combined high-throughput and high-content platform for unified on-chip synthesis, characterization and biological screening

Acceleration and unification of drug discovery is important to reduce the effort and cost of new drug development. Diverse chemical and biological conditions, specialized infrastructure and incompatibility between existing analytical methods with high-throughput, nanoliter scale chemistry make the whole drug discovery process lengthy and expensive. Here, we demonstrate a chemBIOS platform combining on-chip chemical synthesis, characterization and biological screening. We developed a dendrimer-based surface patterning that enables the generation of high-density nanodroplet arrays for both organic and aqueous liquids. Each droplet (among > 50,000 droplets per plate) functions as an individual, spatially separated nanovessel, that can be used for solution-based synthesis or analytical assays. An additional indium-tin oxide coating enables ultra-fast on-chip detection down to the attomole per droplet by matrix-assisted laser desorption/ionization mass spectrometry. The excellent optical properties of the chemBIOS platform allow for on-chip characterization and in-situ reaction monitoring in the ultraviolet, visible (on-chip UV-Vis spectroscopy and optical microscopy) and infrared (on-chip IR spectroscopy) regions. The platform is compatible with various cell-biological screenings, which opens new avenues in the fields of high-throughput synthesis and drug discovery

Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy

BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities

Glassy Vortex State in a Two-Dimensional Disordered XY-Model

The two-dimensional XY-model with random phase-shifts on bonds is studied. The analysis is based on a renormalization group for the replicated system. The model is shown to have an ordered phase with quasi long-range order. This ordered phase consists of a glass-like region at lower temperatures and of a non-glassy region at higher temperatures. The transition from the disordered phase into the ordered phase is not reentrant and is of a new universality class at zero temperature. In contrast to previous approaches the disorder strength is found to be renormalized to larger values. Several correlation functions are calculated for the ordered phase. They allow to identify not only the transition into the glassy phase but also an additional crossover line, where the disconnected vortex correlation changes its behavior on large scales non-analytically. The renormalization group approach yields the glassy features without a breaking of replica symmetry.Comment: latex 12 pages with 3 figures, using epsf.sty and multicol.st

Estimated incidence of previously undetected atrial fibrillation on a 14-day continuous electrocardiographic monitor and associated risk of stroke

Aims There is uncertainty about whether and how to perform screening for atrial fibrillation (AF). To estimate the incidence of previously undetected AF that would be captured using a continuous 14-day ECG monitor and the associated risk of stroke. Methods and results We analysed data from a cohort of patients >65 years old with hypertension and a pacemaker, but without known AF. For each participant, we simulated 1000 ECG monitors by randomly selecting 14-day windows in the 6 months following enrolment and calculated the average AF burden (total time in AF). We used Cox proportional hazards models adjusted for CHA(2)DS(2)-VASc score to estimate the risk of subsequent ischaemic stroke or systemic embolism (SSE) associated with burdens of AF > and 6 min was 3.10% (95% CI 2.53-3.72). This was consistent across strata of age and CHA(2)DS(2)-VASc scores. Over a mean follow-up of 2.4 years, the rate of SSE among patients with 6 min of AF. Conclusions Approximately 3% of individuals aged >65 years with hypertension may have more than 6 min of AF detected by a 14-day ECG monitor. This is associated with a stroke risk of over 2% per year. Whether oral anticoagulation will reduce stroke in these patients is unknown

Darwin -— an experimental astronomy mission to search for extrasolar planets

As a response to ESA call for mission concepts for its Cosmic Vision 2015–2025 plan, we propose a mission called Darwin. Its primary goal is the study of terrestrial extrasolar planets and the search for life on them. In this paper, we describe different characteristics of the instrument

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Road network selection using an extended stroke-mesh combination algorithm

The road network is an essential feature class in topographic maps and databases. Road network selection for smaller scales forms a prerequisite for all other generalization operators and is thus a fundamental operation in the overall process of topographic map and database production. The objective of this paper was to develop an algorithm for automated road network selection from a large-scale (1:10,000) to a medium-scale database (1:50,000). The project was pursued in collaboration with swisstopo, the national mapping agency of Switzerland. Three algorithms (a stroke-based, a mesh-based, and a combined stroke-mesh algorithm) were implemented from the literature and analyzed using swisstopo’s large-scale TLM3D spatial database, with requirements set forth by expert cartographers. Initial experiments showed that the combination algorithm performed best, yet still it could not meet all requirements. Therefore, extensions to the basic stroke-mesh algorithm were developed, significantly improving the selection result with real-world, large test databases. Three extensions introduce modifications to the stroke-mesh combination algorithm. Furthermore, two extensions include external feature classes, ensuring accessibility of points of interest and appropriate network density representation in settlement areas, respectively. The results were evaluated by expert cartographers, who concluded that the proposed approach is ready to be deployed in production at swisstopo

Plasmonic and new plasmonic materials: general discussion

Discussions.-- et al.Peer Reviewe