Chimeric antigen receptors that trigger phagocytosis

Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%

Genomic Stability of Composite SCCmec ACME and COMER-Like Genetic Elements in Staphylococcus epidermidis Correlates With Rate of Excision

NA is supported by a fellowship of the King Saud University (Riyadh, Saudi Arabia). The authors thank the work of the management team of the ALICE High Performance Computing Facility at the University of Leicester. JDR is supported by the BBSRC grant BB/P504737/1. Data AvailabiliTy Statement The datasets generated for this study can be found in the GenBank (accession numbers SAMN12840193–SAMN12840250).Peer reviewedPublisher PD

The Discovery of a Debris Disk Around the DAV White Dwarf PG 1541+651

To search for circumstellar disks around evolved stars, we targeted roughly 100 DA white dwarfs from the Palomar Green survey with the Peters Automated Infrared Imaging Telescope (PAIRITEL). Here we report the discovery of a debris disk around one of these targets, the pulsating white dwarf PG 1541+651 (KX Draconis, hereafter PG1541). We detect a significant flux excess around PG1541 in the K-band. Follow-up near-infrared spectroscopic observations obtained at the NASA Infrared Telescope Facility (IRTF) and photometric observations with the warm Spitzer Space Telescope confirm the presence of a warm debris disk within 0.13-0.36 Rsun (11-32x the stellar radius) at an inclination angle of 60deg. At Teff = 11880 K, PG1541 is almost a twin of the DAV white dwarf G29-38, which also hosts a debris disk. All previously known dusty white dwarfs are of the DAZ/DBZ spectral type due to accretion of metals from the disk. High-resolution optical spectroscopy is needed to search for metal absorption lines in PG1541 and to constrain the accretion rate from the disk. PG1541 is only 55 pc away from the Sun and the discovery of its disk in our survey demonstrates that our knowledge of the nearby dusty white dwarf population is far from complete.Comment: MNRAS Letters, in pres

Spatial control of Draper receptor signaling initiates apoptotic cell engulfment.

The engulfment of apoptotic cells is essential for tissue homeostasis and recovering from damage. Engulfment is mediated by receptors that recognize ligands exposed on apoptotic cells such as phosphatidylserine (PS). In this study, we convert Drosophila melanogaster S2 cells into proficient phagocytes by transfecting the Draper engulfment receptor and replacing apoptotic cells with PS-coated beads. Similar to the T cell receptor (TCR), PS-ligated Draper forms dynamic microclusters that recruit cytosolic effector proteins and exclude a bulky transmembrane phosphatase, consistent with a kinetic segregation-based triggering mechanism. However, in contrast with the TCR, localized signaling at Draper microclusters results in time-dependent depletion of actin filaments, which facilitates engulfment. The Draper-PS extracellular module can be replaced with FRB and FKBP, respectively, resulting in a rapamycin-inducible engulfment system that can be programmed toward defined targets. Collectively, our results reveal mechanistic similarities and differences between the receptors involved in apoptotic corpse clearance and mammalian immunity and demonstrate that engulfment can be reprogrammed toward nonnative targets

Neutrophils are Mediators of Metastatic Prostate Cancer Progression in Bone

Bone metastatic prostate cancer (BM-PCa) significantly reduces overall patient survival and is currently incurable. Current standard immunotherapy showed promising results for PCa patients with metastatic, but less advanced, disease (i.e., fewer than 20 bone lesions) suggesting that PCa growth in bone contributes to response to immunotherapy. We found that: (1) PCa stimulates recruitment of neutrophils, the most abundant immune cell in bone, and (2) that neutrophils heavily infiltrate regions of prostate tumor in bone of BM-PCa patients. Based on these findings, we examined the impact of direct neutrophil-prostate cancer interactions on prostate cancer growth. Bone marrow neutrophils directly induced apoptosis of PCa in vitro and in vivo, such that neutrophil depletion in bone metastasis models enhanced BM-PCa growth. Neutrophil-mediated PCa killing was found to be mediated by suppression of STAT5, a transcription factor shown to promote PCa progression. However, as the tumor progressed in bone over time, neutrophils from late-stage bone tumors failed to elicit cytotoxic effector responses to PCa. These findings are the first to demonstrate that bone-resident neutrophils inhibit PCa and that BM-PCa are able to progress via evasion of neutrophil-mediated killing. Enhancing neutrophil cytotoxicity in bone may present a novel therapeutic option for bone metastatic prostate cancer

DGIdb 5.0: Rebuilding the Drug-Gene Interaction Database for precision medicine and drug discovery platforms

The Drug-Gene Interaction Database (DGIdb, https://dgidb.org) is a publicly accessible resource that aggregates genes or gene products, drugs and drug-gene interaction records to drive hypothesis generation and discovery for clinicians and researchers. DGIdb 5.0 is the latest release and includes substantial architectural and functional updates to support integration into clinical and drug discovery pipelines. The DGIdb service architecture has been split into separate client and server applications, enabling consistent data access for users of both the application programming interface (API) and web interface. The new interface was developed in ReactJS, and includes dynamic visualizations and consistency in the display of user interface elements. A GraphQL API has been added to support customizable queries for all drugs, genes, annotations and associated data. Updated documentation provides users with example queries and detailed usage instructions for these new features. In addition, six sources have been added and many existing sources have been updated. Newly added sources include ChemIDplus, HemOnc, NCIt (National Cancer Institute Thesaurus), Drugs@FDA, HGNC (HUGO Gene Nomenclature Committee) and RxNorm. These new sources have been incorporated into DGIdb to provide additional records and enhance annotations of regulatory approval status for therapeutics. Methods for grouping drugs and genes have been expanded upon and developed as independent modular normalizers during import. The updates to these sources and grouping methods have resulted in an improvement in FAIR (findability, accessibility, interoperability and reusability) data representation in DGIdb

A dynamic microsimulation model for epidemics.

Funder: Aerospace Technology InstituteFunder: UK Research and InnovationFunder: The Alan Turing InstituteA large evidence base demonstrates that the outcomes of COVID-19 and national and local interventions are not distributed equally across different communities. The need to inform policies and mitigation measures aimed at reducing the spread of COVID-19 highlights the need to understand the complex links between our daily activities and COVID-19 transmission that reflect the characteristics of British society. As a result of a partnership between academic and private sector researchers, we introduce a novel data driven modelling framework together with a computationally efficient approach to running complex simulation models of this type. We demonstrate the power and spatial flexibility of the framework to assess the effects of different interventions in a case study where the effects of the first UK national lockdown are estimated for the county of Devon. Here we find that an earlier lockdown is estimated to result in a lower peak in COVID-19 cases and 47% fewer infections overall during the initial COVID-19 outbreak. The framework we outline here will be crucial in gaining a greater understanding of the effects of policy interventions in different areas and within different populations

Economic immorality and social reformation in English popular preaching, 1585-1625

Popular preachers, often drawing crowds of hundreds, frequently attempted to reform the relationship between rich and poor in Elizabethan and Jacobean England. Rather than accepting economic oppression as part of the divinely-ordained social order, many tried to convince their audiences that the extortions of merchants, landlords and creditors were crimes which should be punished severely by England’s earthly authorities. This paper demonstrates how the language of popular homiletics opened up a space for plebeian action with concrete socioeconomic consequences. By analysing the connotative idiom of social complaint found in homilies and other widely-heard sermons, the important but historiographically neglected role of ‘godliness’ in the early modern ‘moral economy’ is revealed

Photometric redshifts and quasar probabilities from a single, data-driven generative model

We describe a technique for simultaneously classifying and estimating the redshift of quasars. It can separate quasars from stars in arbitrary redshift ranges, estimate full posterior distribution functions for the redshift, and naturally incorporate flux uncertainties, missing data, and multi-wavelength photometry. We build models of quasars in flux-redshift space by applying the extreme deconvolution technique to estimate the underlying density. By integrating this density over redshift one can obtain quasar flux-densities in different redshift ranges. This approach allows for efficient, consistent, and fast classification and photometric redshift estimation. This is achieved by combining the speed obtained by choosing simple analytical forms as the basis of our density model with the flexibility of non-parametric models through the use of many simple components with many parameters. We show that this technique is competitive with the best photometric quasar classification techniques---which are limited to fixed, broad redshift ranges and high signal-to-noise ratio data---and with the best photometric redshift techniques when applied to broadband optical data. We demonstrate that the inclusion of UV and NIR data significantly improves photometric quasar--star separation and essentially resolves all of the redshift degeneracies for quasars inherent to the ugriz filter system, even when included data have a low signal-to-noise ratio. For quasars spectroscopically confirmed by the SDSS 84 and 97 percent of the objects with GALEX UV and UKIDSS NIR data have photometric redshifts within 0.1 and 0.3, respectively, of the spectroscopic redshift; this amounts to about a factor of three improvement over ugriz-only photometric redshifts. Our code to calculate quasar probabilities and redshift probability distributions is publicly available