Multiplexed Detection of Analytes on Single Test Strips with Antibody-Gated Indicator-Releasing Mesoporous Nanoparticles

This is the peer reviewed version of the following article: Climent, E., Biyikal, M., Gröninger, D., Weller, M. G., Martínez¿Máñez, R., & Rurack, K. (2020). Multiplexed Detection of Analytes on Single Test Strips with Antibody-Gated Indicator-Releasing Mesoporous Nanoparticles. Angewandte Chemie International Edition, 59(52), 23862-23869, which has been published in final form at https://doi.org/10.1002/anie.202009000. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] Rapid testing methods for the use directly at a point of need are expected to unfold their true potential especially when offering adequate capabilities for the simultaneous measurement of multiple analytes of interest. Considering the unique modularity, high sensitivity, and selectivity of antibody-gated indicator delivery (gAID) systems, a multiplexed assay for three small-molecule explosives (TATP, TNT, PETN) was thus developed, allowing to detect the analytes simultaneously with a single test strip at lower ppb concentrations in the liquid phase in 2 adsorption/desorption measurements, Y. Salinas and L. E. Santos for support on the materials screening, A. Walter, S. Ramin and A. Hesse for obtaining the sera and R. Gotor and J. Bell for their help in the fabrication of the home-made smartphone periphery. Open access funding enabled and organized by Projekt DEAL.Climent Terol, E.; Biyikal, M.; Gröninger, D.; Weller, MG.; Martínez-Máñez, R.; Rurack, K. (2020). Multiplexed Detection of Analytes on Single Test Strips with Antibody-Gated Indicator-Releasing Mesoporous Nanoparticles. Angewandte Chemie International Edition. 59(52):23862-23869. https://doi.org/10.1002/anie.2020090002386223869595

Using learning environments as a metaphor for educational change

Purpose – The purpose of this paper is to show that the online learning environment can be seen as the means by which higher education can explore the challenges and opportunities raised by online and digital society. Design/methodology/approach – The paper argues that the online learning environment can be seen as a metaphor for how universities respond to the requirements and challenges of the digital age. Current learning management systems (LMSs) are examined, and compared with the values found in web 2.0 and social media. Current thinking on pedagogy for online learning is then examined. The SocialLearn project at the Open University in the UK is then explained, which seeks to create a disaggregated, decentralised, social system for learners. Findings – The conclusion from the analysis is that there is a conflict between the centralised learning management system (LMS) and the requirements of online pedagogy. The traditional LMS can be seen as embodying the wrong metaphor, that of the traditional classroom. The paper concludes by arguing that such learning environments will be more useful to higher education in coming to understand its response to many of the changes being seen in society, which are facilitated by the new technologies. Originality/value – The paper provides a framework for considering LMSs and their relation to universities and pedagogy, and an argument for the promotion of more decentralised systems

Investigations of the copper peptide hepcidin-25 by LC-MS/MS and NMR+

Hepcidin-25 was identified as the main iron regulator in the human body, and it by binds to the sole iron-exporter ferroportin. Studies showed that the N-terminus of hepcidin is responsible for this interaction, the same N-terminus that encompasses a small copper(II)-binding site known as the ATCUN (amino-terminal Cu(II)- and Ni(II)-binding) motif. Interestingly, this copper-binding property is largely ignored in most papers dealing with hepcidin-25. In this context, detailed investigations of the complex formed between hepcidin-25 and copper could reveal insight into its biological role. The present work focuses on metal-bound hepcidin-25 that can be considered the biologically active form. The first part is devoted to the reversed-phase chromatographic separation of copper-bound and copper-free hepcidin-25 achieved by applying basic mobile phases containing 0.1% ammonia. Further, mass spectrometry (tandem mass spectrometry (MS/MS), high-resolution mass spectrometry (HRMS)) and nuclear magnetic resonance (NMR) spectroscopy were employed to characterize the copper-peptide. Lastly, a three-dimensional (3D) model of hepcidin-25 with bound copper(II) is presented. The identification of metal complexes and potential isoforms and isomers, from which the latter usually are left undetected by mass spectrometry, led to the conclusion that complementary analytical methods are needed to characterize a peptide calibrant or reference material comprehensively. Quantitative nuclear magnetic resonance (qNMR), inductively-coupled plasma mass spectrometry (ICP-MS), ion-mobility spectrometry (IMS) and chiral amino acid analysis (AAA) should be considered among others

Separate Universes Do Not Constrain Primordial Black Hole Formation

Carr and Hawking showed that the proper size of a spherical overdense region surrounded by a flat FRW universe cannot be arbitrarily large as otherwise the region would close up on itself and become a separate universe. From this result they derived a condition connecting size and density of the overdense region ensuring that it is part of our universe. Carr used this condition to obtain an upper bound for the density fluctuation amplitude with the property that for smaller amplitudes the formation of a primordial black hole is possible, while larger ones indicate a separate universe. In contrast, we find that the appearance of a maximum is not a consequence of avoiding separate universes but arises naturally from the geometry of the chosen slicing. Using instead of density a volume fluctuation variable reveals that a fluctuation is a separate universe iff this variable diverges on superhorizon scales. Hence Carr's and Hawking's condition does not pose a physical constraint on density fluctuations. The dynamics of primordial black hole formation with an initial curvature fluctuation amplitude larger than the one corresponding to the maximum density fluctuation amplitude was previously not considered in detail and so we compare it to the well-known case where the amplitude is smaller by presenting embedding and conformal diagrams of both types in dust spacetimes.Comment: Updated version corresponds to the published version 10.1103/PhysRevD.83.124025, 22 pages, 22 figure

The Passing of Print

This paper argues that ephemera is a key instrument of cultural memory, marking the things intended to be forgotten. This important role means that when ephemera survives, whether accidentally or deliberately, it does so despite itself. These survivals, because they evoke all those other objects that have necessarily been forgotten, can be described as uncanny. The paper is divided into three main sections. The first situates ephemera within an uncanny economy of memory and forgetting. The second focuses on ephemera at a particular historical moment, the industrialization of print in the nineteenth century. This section considers the liminal place of newspapers and periodicals in this period, positioned as both provisional media for information as well as objects of record. The third section introduces a new configuration of technologies – scanners, computers, hard disks, monitors, the various connections between them – and considers the conditions under which born-digital ephemera can linger and return. Through this analysis, the paper concludes by considering digital technologies as an apparatus of memory, setting out what is required if we are not to be doubly haunted by the printed ephemera within the digital archive

Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors. METHODS: CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models. RESULTS: We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals. CONCLUSIONS: These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology

Explaining global surface aerosol number concentrations in terms of primary emissions and particle formation

We use observations of total particle number concentration at 36 worldwide sites and a global aerosol model to quantify the primary and secondary sources of particle number. We show that emissions of primary particles can reasonably reproduce the spatial pattern of observed condensation nuclei (CN) (R2=0.51) but fail to explain the observed seasonal cycle at many sites (R2=0.1). The modeled CN concentration in the free troposphere is biased low (normalised mean bias, NMB=−88%) unless a secondary source of particles is included, for example from binary homogeneous nucleation of sulfuric acid and water (NMB=−25%). Simulated CN concentrations in the continental boundary layer (BL) are also biased low (NMB=−74%) unless the number emission of anthropogenic primary particles is increased or an empirical BL particle formation mechanism based on sulfuric acid is used. We find that the seasonal CN cycle observed at continental BL sites is better simulated by including a BL particle formation mechanism (R2=0.3) than by increasing the number emission from primary anthropogenic sources (R2=0.18). Using sensitivity tests we derive optimum rate coefficients for this nucleation mechanism, which agree with values derived from detailed case studies at individual sites

The Fermi GBM Gamma-Ray Burst Spectral Catalog: Four Years Of Data

In this catalog we present the updated set of spectral analyses of GRBs detected by the Fermi Gamma-Ray Burst Monitor (GBM) during its first four years of operation. It contains two types of spectra, time-integrated spectral fits and spectral fits at the brightest time bin, from 943 triggered GRBs. Four different spectral models were fitted to the data, resulting in a compendium of more than 7500 spectra. The analysis was performed similarly, but not identically to Goldstein et al. 2012. All 487 GRBs from the first two years have been re-fitted using the same methodology as that of the 456 GRBs in years three and four. We describe, in detail, our procedure and criteria for the analysis, and present the results in the form of parameter distributions both for the observer-frame and rest-frame quantities. The data files containing the complete results are available from the High-Energy Astrophysics Science Archive Research Center (HEASARC).Comment: Accepted for publication in ApJ

Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene

Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene.BackgroundWe have recently identified a mutation in the uromodulin gene in a large family affected with hyperuricemia, gout, and renal failure. The purpose of this investigation is to provide a comprehensive characterization of the clinical findings of this syndrome in family members who had a mutation in the uromodulin gene.MethodsAn extended family suffering from hyperuricemia and gout was identified by a local practitioner. After consent was obtained, patients provided a directed clinical history and blood and urine specimens for chemical and genetic testing. All family members were tested for the presence of uromodulin gene mutations by direct DNA sequence analysis. The clinical and biochemical characteristics of family members carrying the affected mutation were then investigated.ResultsThirty-nine family members were found to have an exon 5 uromodulin gene mutation (g.1966 1922 del), and 29 unaffected family members were identified. The cardinal clinical features in individuals with the uromodulin mutation included hyperuricemia, decreased fractional excretion of uric acid, and chronic interstitial renal disease leading to end-stage renal disease (ESRD) in the fifth through seventh decade. Women did not always develop hyperuricemia or gout, but still developed progressive chronic renal failure.ConclusionMutation of the uromodulin gene resulted in hyperuricemia, reduced fractional excretion of uric acid, and renal failure. Genetic testing will be required to definitively identify individuals suffering from this condition. We are interested in studying other families that may suffer from this condition and would appreciate any such referrals