Measurement of the very rare K+→π+ννˉK^+ \to \pi^+ \nu \bar\nu decay

The decay K+→π+νν¯ , with a very precisely predicted branching ratio of less than 10−10 , is among the best processes to reveal indirect effects of new physics. The NA62 experiment at CERN SPS is designed to study the K+→π+νν¯ decay and to measure its branching ratio using a decay-in-flight technique. NA62 took data in 2016, 2017 and 2018, reaching the sensitivity of the Standard Model for the K+→π+νν¯ decay by the analysis of the 2016 and 2017 data, and providing the most precise measurement of the branching ratio to date by the analysis of the 2018 data. This measurement is also used to set limits on BR(K+→π+X ), where X is a scalar or pseudo-scalar particle. The final result of the BR(K+→π+νν¯ ) measurement and its interpretation in terms of the K+→π+X decay from the analysis of the full 2016-2018 data set is presented, and future plans and prospects are reviewed

Heparan Sulfate Facilitates Binding of hIFNγ to Its Cell-Surface Receptor hIFNGR1

Human interferon-gamma (hIFNγ) is a crucial signaling molecule with an important role in the initialization and development of the immune response of the host. However, its aberrant activity is also associated with the progression of a multitude of autoimmune and other diseases, which determines the need for effective inhibitors of its activity. The development of such treatments requires proper understanding of the interaction of hIFNγ to its cell-surface receptor hIFNGR1. Currently, there is no comprehensive model of the mechanism of this binding process. Here, we employ molecular dynamics simulations to study on a microscopic level the process of hIFNγ–hIFNGR1 complex formation in different scenarios. We find that the two molecules alone fail to form a stable complex, but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity assay on cells depleted from cell-surface heparan sulfate (HS) sulfation together with the phosphorylation levels of the signal transducer and activator of transcription STAT1 confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling

His-FLAG Tag as a Fusion Partner of Glycosylated Human Interferon-Gamma and Its Mutant: Gain or Loss?

In order to obtain glycosylated human interferon-gamma (hIFNγ) and its highly prone to aggregation mutant K88Q, a secretory expression in insect cells was employed. To facilitate recombinant proteins purification, detection, and stability the baculovirus expression vectors were constructed to bear N-terminal His6-FLAG tag. Although the obtained proteins were glycosylated, we found that their biological activity was 100 times lower than expected. Our attempts to recover the biological properties of both proteins by tag removal failed due to enterokinase resistance of the tag. Surprisingly, the tag was easily cleaved when the proteins were expressed in E. coli cells and the tag-free proteins showed fully restored activity. To shed light on this phenomenon we performed molecular dynamics simulations. The latter showed that the tags interact with the receptor binding domains and the flexible C-termini of the fusion proteins thus suppressing their complex formation with the hIFNγ receptor. We hypothesize that in the case of glycosylated proteins the tag/C-terminal interaction positions the FLAG peptide in close proximity to the glycans thus sterically impeding the enterokinase access to its recognition site

Molecular Mechanism of the Anti-Inflammatory Action of Heparin

Our objective is to reveal the molecular mechanism of the anti-inflammatory action of low-molecular-weight heparin (LMWH) based on its influence on the activity of two key cytokines, IFNγ and IL-6. The mechanism of heparin binding to IFNγ and IL-6 and the resulting inhibition of their activity were studied by means of extensive molecular-dynamics simulations. The effect of LMWH on IFNγ signalling inside stimulated WISH cells was investigated by measuring its antiproliferative activity and the translocation of phosphorylated STAT1 in the nucleus. We found that LMWH binds with high affinity to IFNγ and is able to fully inhibit the interaction with its cellular receptor. It also influences the biological activity of IL-6 by binding to either IL-6 or IL-6/IL-6Rα, thus preventing the formation of the IL-6/IL-6Rα/gp130 signalling complex. These findings shed light on the molecular mechanism of the anti-inflammatory action of LMWH and underpin its ability to influence favourably conditions characterised by overexpression of these two cytokines. Such conditions are not only associated with autoimmune diseases, but also with inflammatory processes, in particular with COVID-19. Our results put forward heparin as a promising means for the prevention and suppression of severe CRS and encourage further investigations on its applicability as an anti-inflammatory agent

Availability of technology for managing cancer patients in the Southeast European (SEE) region

Background: The Southeast European (SEE) region of 10 countries and about 43 million people differs from Western Europe in that most SEE countries lack active cancer registries and have fewer diagnostic imaging devices and radiotherapy (RT) units. The main objective of this research is to initiate a common platform for gathering SEE regional cancer data from the ground up to help these countries develop common cancer management strategies. Methods: To obtain detailed on-the-ground information, we developed separate questionnaires for two SEE groups: a) ONCO - oncologists regarding cancer treatment modalities and the availability of diagnostic imaging and radiotherapy equipment; and b) REG - national radiation protection and safety regulatory bodies regarding diagnostic imaging and radiotherapy equipment in SEE facilities. Results: Based on responses from 13/17 ONCO participants (at least one from each country) and from 9/10 REG participants (all countries but Albania), cancer incidence rates are higher in those SEE countries that have greater access to diagnostic imaging equipment while cancer mortality-to-incidence (MIR) ratios are higher in countries that lack radiotherapy equipment. Conclusion: By combining unique SEE region information with data available from major global databases, we demonstrated that the availability of diagnostic imaging and radiotherapy equipment in the SEE countries is related to their economic development. While immediate diagnostic imaging and radiation therapy capacity building is necessary, it is also essential to develop both national and SEE-regional cancer registries in order to understand the heterogeneity of each country’s needs and to establish regional collaborative strategies for combating cancer

Search for heavy neutrinos in K+→μ+νμK^+ \rightarrow \mu^+ \nu_{\mu} decays

International audienceThe NA62 experiment recorded a large sample of K+→μ+νμ decays in 2007. A peak search has been performed in the reconstructed missing mass spectrum. In the absence of a signal, limits in the range 2×10−6 to 10−5 have been set on the squared mixing matrix element |Uμ4|2 between muon and heavy neutrino states, for heavy neutrino masses in the range 300–375 MeV/ c2 . The result extends the range of masses for which upper limits have been set on the value of |Uμ4|2 in previous production search experiments