Cell-type specific potent Wnt signaling blockade by bispecific antibody.

Cell signaling pathways are often shared between normal and diseased cells. How to achieve cell type-specific, potent inhibition of signaling pathways is a major challenge with implications for therapeutic development. Using the Wnt/β-catenin signaling pathway as a model system, we report here a novel and generally applicable method to achieve cell type-selective signaling blockade. We constructed a bispecific antibody targeting the Wnt co-receptor LRP6 (the effector antigen) and a cell type-associated antigen (the guide antigen) that provides the targeting specificity. We found that the bispecific antibody inhibits Wnt-induced reporter activities with over one hundred-fold enhancement in potency, and in a cell type-selective manner. Potency enhancement is dependent on the expression level of the guide antigen on the target cell surface and the apparent affinity of the anti-guide antibody. Both internalizing and non-internalizing guide antigens can be used, with internalizing bispecific antibody being able to block signaling by all ligands binding to the target receptor due to its removal from the cell surface. It is thus feasible to develop bispecific-based therapeutic strategies that potently and selectively inhibit signaling pathways in a cell type-selective manner, creating opportunity for therapeutic targeting

The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach

The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271–294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed.</jats:p

Possible thermochemical disequilibrium in the atmosphere of the exoplanet GJ 436b

The nearby extrasolar planet GJ 436b--which has been labelled as a 'hot Neptune'--reveals itself by the dimming of light as it crosses in front of and behind its parent star as seen from Earth. Respectively known as the primary transit and secondary eclipse, the former constrains the planet's radius and mass, and the latter constrains the planet's temperature and, with measurements at multiple wavelengths, its atmospheric composition. Previous work using transmission spectroscopy failed to detect the 1.4-\mu m water vapour band, leaving the planet's atmospheric composition poorly constrained. Here we report the detection of planetary thermal emission from the dayside of GJ 436b at multiple infrared wavelengths during the secondary eclipse. The best-fit compositional models contain a high CO abundance and a substantial methane (CH4) deficiency relative to thermochemical equilibrium models for the predicted hydrogen-dominated atmosphere. Moreover, we report the presence of some H2O and traces of CO2. Because CH4 is expected to be the dominant carbon-bearing species, disequilibrium processes such as vertical mixing and polymerization of methane into substances such as ethylene may be required to explain the hot Neptune's small CH4-to-CO ratio, which is at least 10^5 times smaller than predicted

Exoplanet phase curves: observations and theory

Phase curves are the best technique to probe the three dimensional structure of exoplanets' atmospheres. In this chapter we first review current exoplanets phase curve observations and the particular challenges they face. We then describe the different physical mechanisms shaping the atmospheric phase curves of highly irradiated tidally locked exoplanets. Finally, we discuss the potential for future missions to further advance our understanding of these new worlds.Comment: Fig.5 has been updated. Table 1 and corresponding figures have been updated with new values for WASP-103b and WASP-18b. Contains a table sumarizing phase curve observation

Photon Management in Two-Dimensional Disordered Media

Elaborating reliable and versatile strategies for efficient light coupling between free space and thin films is of crucial importance for new technologies in energy efficiency. Nanostructured materials have opened unprecedented opportunities for light management, notably in thin-film solar cells. Efficient coherent light trapping has been accomplished through the careful design of plasmonic nanoparticles and gratings, resonant dielectric particles and photonic crystals. Alternative approaches have used randomly-textured surfaces as strong light diffusers to benefit from their broadband and wide-angle properties. Here, we propose a new strategy for photon management in thin films that combines both advantages of an efficient trapping due to coherent optical effects and broadband/wide-angle properties due to disorder. Our approach consists in the excitation of electromagnetic modes formed by multiple light scattering and wave interference in two-dimensional random media. We show, by numerical calculations, that the spectral and angular responses of thin films containing disordered photonic patterns are intimately related to the in-plane light transport process and can be tuned through structural correlations. Our findings, which are applicable to all waves, are particularly suited for improving the absorption efficiency of thin-film solar cells and can provide a novel approach for high-extraction efficiency light-emitting diodes

Universal logic with encoded spin qubits in silicon

Qubits encoded in a decoherence-free subsystem and realized in exchange-coupled silicon quantum dots are promising candidates for fault-tolerant quantum computing. Benefits of this approach include excellent coherence, low control crosstalk, and configurable insensitivity to certain error sources. Key difficulties are that encoded entangling gates require a large number of control pulses and high-yielding quantum dot arrays. Here we show a device made using the single-layer etch-defined gate electrode architecture that achieves both the required functional yield needed for full control and the coherence necessary for thousands of calibrated exchange pulses to be applied. We measure an average two-qubit Clifford fidelity of $97.1 \pm 0.2\%$ with randomized benchmarking. We also use interleaved randomized benchmarking to demonstrate the controlled-NOT gate with $96.3 \pm 0.7\%$ fidelity, SWAP with $99.3 \pm 0.5\%$ fidelity, and a specialized entangling gate that limits spreading of leakage with $93.8 \pm 0.7\%$ fidelity

Haemoglobin C and S Role in Acquired Immunity against Plasmodium falciparum Malaria

A recently proposed mechanism of protection for haemoglobin C (HbC; β6Glu→Lys) links an abnormal display of PfEMP1, an antigen involved in malaria pathogenesis, on the surface of HbC infected erythrocytes together with the observation of reduced cytoadhesion of parasitized erythrocytes and impaired rosetting in vitro. We investigated the impact of this hypothesis on the development of acquired immunity against Plasmodium falciparum variant surface antigens (VSA) encoding PfEMP1 in HbC in comparison with HbA and HbS carriers of Burkina Faso. We measured: i) total IgG against a single VSA, A4U, and against a panel of VSA from severe malaria cases in human sera from urban and rural areas of Burkina Faso of different haemoglobin genotypes (CC, AC, AS, SC, SS); ii) total IgG against recombinant proteins of P. falciparum asexual sporozoite, blood stage antigens, and parasite schizont extract; iii) total IgG against tetanus toxoid. Results showed that the reported abnormal cell-surface display of PfEMP1 on HbC infected erythrocytes observed in vitro is not associated to lower anti- PfEMP1 response in vivo. Higher immune response against the VSA panel and malaria antigens were observed in all adaptive genotypes containing at least one allelic variant HbC or HbS in the low transmission urban area whereas no differences were detected in the high transmission rural area. In both contexts the response against tetanus toxoid was not influenced by the β-globin genotype. These findings suggest that both HbC and HbS affect the early development of naturally acquired immunity against malaria. The enhanced immune reactivity in both HbC and HbS carriers supports the hypothesis that the protection against malaria of these adaptive genotypes might be at least partially mediated by acquired immunity against malaria

4D Flow cardiovascular magnetic resonance consensus statement: 2023 update

Hemodynamic assessment is an integral part of the diagnosis and management of cardiovascular disease. Four-dimensional cardiovascular magnetic resonance flow imaging (4D Flow CMR) allows comprehensive and accurate assessment of flow in a single acquisition. This consensus paper is an update from the 2015 '4D Flow CMR Consensus Statement'. We elaborate on 4D Flow CMR sequence options and imaging considerations. The document aims to assist centers starting out with 4D Flow CMR of the heart and great vessels with advice on acquisition parameters, post-processing workflows and integration into clinical practice. Furthermore, we define minimum quality assurance and validation standards for clinical centers. We also address the challenges faced in quality assurance and validation in the research setting. We also include a checklist for recommended publication standards, specifically for 4D Flow CMR. Finally, we discuss the current limitations and the future of 4D Flow CMR. This updated consensus paper will further facilitate widespread adoption of 4D Flow CMR in the clinical workflow across the globe and aid consistently high-quality publication standards

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets