Galectin-9 promotes natural killer cells activity via interaction with CD44.

Natural killer (NK) cells are a potent innate source of cytokines and cytoplasmic granules. Their effector functions are tightly synchronized by the balance between the stimulatory and inhibitory receptors. Here, we quantified the proportion of NK cells and the surface presence of Galectin-9 (Gal-9) from the bone marrow, blood, liver, spleen, and lungs of adult and neonatal mice. We also examined the effector functions of Gal-9+NK cells compared with their Gal-9- counterparts. Our results revealed that Gal-9+NK cells are more abundant in tissues, in particular, in the liver than in the blood and bone marrow. We found Gal-9 presence was associated with enhanced cytotoxic effector molecules granzyme B (GzmB) and perforin expression. Likewise, Gal-9 expressing NK cells displayed greater IFN-γ and TNF-α expression than their negative counterparts under hemostatic circumstances. Notably, the expansion of Gal-9+NK cells in the spleen of mice infected with E. coli implies that Gal-9+NK cells may provide a protective role against infection. Similarly, we found the expansion of Gal-9+NK cells in the spleen and tumor tissues of melanoma B16-F10 mice. Mechanistically, our results revealed the interaction of Gal-9 with CD44 as noted by their co-expression/co-localization. Subsequently, this interaction resulted in enhanced expression of Phospho-LCK, ERK, Akt, MAPK, and mTOR in NK cells. Moreover, we found Gal-9+NK cells exhibited an activated phenotype as evidenced by increased CD69, CD25, and Sca-1 but reduced KLRG1 expression. Likewise, we found Gal-9 preferentially interacts with CD44high in human NK cells. Despite this interaction, we noted a dichotomy in terms of effector functions in NK cells from COVID-19 patients. We observed that the presence of Gal-9 on NK cells resulted in a greater IFN-γ expression without any changes in cytolytic molecule expression in these patients. These observations suggest differences in Gal-9+NK cell effector functions between mice and humans that should be considered in different physiological and pathological conditions. Therefore, our results highlight the important role of Gal-9 via CD44 in NK cell activation, which suggests Gal-9 is a potential new avenue for the development of therapeutic approaches to modulate NK cell effector functions.

Arena3Dweb: interactive 3D visualization of multilayered networks.

Efficient integration and visualization of heterogeneous biomedical information in a single view is a key challenge. In this study, we present Arena3Dweb, the first, fully interactive and dependency-free, web application which allows the visualization of multilayered graphs in 3D space. With Arena3Dweb, users can integrate multiple networks in a single view along with their intra- and inter-layer connections. For clearer and more informative views, users can choose between a plethora of layout algorithms and apply them on a set of selected layers either individually or in combination. Users can align networks and highlight node topological features, whereas each layer as well as the whole scene can be translated, rotated and scaled in 3D space. User-selected edge colors can be used to highlight important paths, while node positioning, coloring and resizing can be adjusted on-the-fly. In its current version, Arena3Dweb supports weighted and unweighted undirected graphs and is written in R, Shiny and JavaScript. We demonstrate the functionality of Arena3Dweb using two different use-case scenarios; one regarding drug repurposing for SARS-CoV-2 and one related to GPCR signaling pathways implicated in melanoma. Arena3Dweb is available at http://bib.fleming.gr:3838/Arena3D or http://bib.fleming.gr/Arena3D.

A digital single-molecule nanopillar SERS platform for predicting and monitoring immune toxicities in immunotherapy.

The introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients.

Aviator: a web service for monitoring the availability of web services.

With Aviator, we present a web service and repository that facilitates surveillance of online tools. Aviator consists of a user-friendly website and two modules, a literature-mining based general and a manually curated module. The general module currently checks 9417 websites twice a day with respect to their availability and stores many features (frontend and backend response time, required RAM and size of the web page, security certificates, analytic tools and trackers embedded in the webpage and others) in a data warehouse. Aviator is also equipped with an analysis functionality, for example authors can check and evaluate the availability of their own tools or those of their peers. Likewise, users can check the availability of a certain tool they intend to use in research or teaching to avoid including unstable tools. The curated section of Aviator offers additional services. We provide API snippets for common programming languages (Perl, PHP, Python, JavaScript) as well as an OpenAPI documentation for embedding in the backend of own web services for an automatic test of their function. We query the respective APIs twice a day and send automated notifications in case of an unexpected result. Naturally, the same analysis functionality as for the literature-based module is available for the curated section. Aviator can freely be used at https://www.ccb.uni-saarland.de/aviator.