PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells

Epithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3−/− mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

'Click'-inspired chemistry in macromolecular science: matching recent progress and user expectations

This year, it has been a decade that the concept of click chemistry was pioneered in polymer and material science by the exploration of the synthetic scope of copper-catalyzed azide/alkyne cycloaddition (CuAAC), the click benchmark. The impact on the endeavors of polymer chemists has been substantial because the power of this concept, featuring modularity, orthogonality, and versatility for the design and synthesis of polymeric materials, was recognized very soon in macromolecular research groups worldwide. After this first burst of research activity, challenging the boundaries of CuAAC in terms of attainable polymer constructs, ongoing method development, and implementation, in response to the need for metal-free alternatives, resulted in a valuable toolbox of click-inspired conjugation methods. Because of the large diversity of employable reactions, applied in various polymeric systems, the first-time or occasional click user will be confronted with a burden of choice. Therefore, the principal aim of this Perspective is to clearly denote the recent progress of click-inspired chemistry in macromolecular science by detailed conceptual analysis and to provide some selection procedures, allowing potential users to readily match their expectations of click chemistry to the state-of-the-art. Consequently, first-time or occasional users should be able to identify and select the most appropriate click-inspired reaction for their purposes and eventually contribute to the next generations of advanced polymeric materials

BioTIME:a database of biodiversity time series for the Anthropocene

Abstract Motivation: The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community‐led open‐source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene. Main types of variables included: The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record. Spatial location and grain: BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km² (158 cm²) to 100 km² (1,000,000,000,000 cm²). Time period and grain: BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year. Major taxa and level of measurement: BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates. Software format: .csv and .SQL

Are rare species useful species? Obstacles to the conservation of tree diversity in the dry forest zone agro-ecosystems of Mesoamerica

Aim To test the potential to conserve rare dry forest tree and shrub species circa situm.Location Oaxaca, Mexico and Southern Honduras.Methods Local uses (timber, posts and firewood) of species were determined principally through semistructured interviews with 20 rural householders in each of four communities in Honduras and four in Oaxaca. Tree and shrub diversity inventories were carried out in a total of 227 forest patches and parcels of farmland in those eight communities. Species’ conservation priorities were determined using the star system of Hawthorne (1996) and IUCN listings.Results Despite a large number of useful species, remarkably few were also conservation priorities. Useful species were found to be substitutable as is illustrated by Bombacopsis quinata, Cordia alliodora, Guaiacum sanctum and G. coulteri.Conclusions In these areas, circa situm conservation is inhibited by the lack of species that are both rare and useful. Usefulness must be interpreted as a function of substitutability. Natural regeneration provides an abundance of diversity, farmers are unlikely to invest in the management of a species when suitable substitutes are freely available. The key to conserving rare species may be in maintaining or enhancing the value of the landscape elements in which they are found