Immunometabolism modulation in therapy

The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions

On the coherence loss in phase-referenced VLBI observations

Context: Phase referencing is a standard calibration technique in radio interferometry, particularly suited for the detection of weak sources close to the sensitivity limits of the interferometers. However, effects from a changing atmosphere and inaccuracies in the correlator model may affect the phase-referenced images, leading to wrong estimates of source flux densities and positions. A systematic observational study of signal decoherence in phase referencing, and its effects in the image plane, has not been performed yet. Aims: We systematically studied how the signal coherence in Very-Long-Baseline-Interferometry (VLBI) observations is affected by a phase-reference calibration at different frequencies and for different calibrator-to-target separations. The results obtained should be of interest for a correct interpretation of many phase-referenced observations with VLBI. Methods: We observed a set of 13 strong sources (the S5 polar cap sample) at 8.4 and 15 GHz in phase-reference mode, with 32 different calibrator/target combinations spanning angular separations between 1.5 and 20.5 degrees. We obtained phase-referenced images and studied how the dynamic range and peak flux density depend on observing frequency and source separation. Results: We obtained dynamic ranges and peak flux densities of the phase-referenced images as a function of frequency and separation from the calibrator. We compared our results with models and phenomenological equations previously reported. Conclusions: The dynamic range of the phase-referenced images is strongly limited by the atmosphere at all frequencies and for all source separations. The limiting dynamic range is inversely proportional to the sine of the calibrator-to-target separation. We also find that the peak flux densities, relative to those obtained with the self-calibrated images, decrease with source separation.Comment: 5 pages, 3 figures. Submitted to A&A on 5.02.2010; accepted on 11.03.2010

Nanodiagnostics to Face SARS-CoV-2 and Future Pandemics: From an Idea to the Market and beyond

The COVID-19 pandemic made clear how our society requires quickly available tools to address emerging healthcare issues. Diagnostic assays and devices are used every day to screen for COVID-19 positive patients, with the aim to decide the appropriate treatment and containment measures. In this context, we would have expected to see the use of the most recent diagnostic technologies worldwide, including the advanced ones such as nano-biosensors capable to provide faster, more sensitive, cheaper, and high-throughput results than the standard polymerase chain reaction and lateral flow assays. Here we discuss why that has not been the case and why all the exciting diagnostic strategies published on a daily basis in peer-reviewed journals are not yet successful in reaching the market and being implemented in the clinical practice.We acknowledge funding from the European Union Horizon2020 Programme under Grant No. 881603 (Graphene Flagship Core 3). We acknowledge Consejo Superior de Investigaciones Científicas (CSIC) for the project “COVID19-122” granted in the call “Nuevas ayudas extraordinarias a proyectos de investigación en el marco de las medidas urgentes extraordinarias para hacer frente al impacto económico y social del COVID-19 (Ayudas CSIC–COVID-19)”. We acknowledge the MICROB-PREDICT Project for partially supporting the work. The MICROB-PREDICT project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant No. 825694. This reflects only the author’s view, and the European Commission is not responsible for any use that may be made of the information it contains. We also acknowledge Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) for the project MAT2017-87202-P. A.I. was supported by a PROBIST postdoctoral fellowship funded by European Research Council (Marie Skłodowska-Curie Grant No. 754510). C.C.C.S. acknowledges funding through CAPES–PRINT (Programa Institucional de Internacionalização; Grant Nos. 88887.310281/2018-00 and 88887.467442/2019-00) and Mackpesquisa-UPM. L.H. acknowledges funding through the China Scholarship Council. ICN2 is funded by the CERCA Programme/Generalitat de Catalunya and supported by the Severo Ochoa programme (MINECO Grant No. SEV-2017-0706)

Structural basis for native agonist and synthetic inhibitor recognition by the Pseudomonas aeruginosa quorum sensing regulator PqsR (MvfR)

Bacterial populations co-ordinate gene expression collectively through quorum sensing (QS), a cell-to-cell communication mechanism employing diffusible signal molecules. The LysR-type transcriptional regulator (LTTR) protein PqsR (MvfR) is a key component of alkyl-quinolone (AQ)-dependent QS in Pseudomonas aeruginosa. PqsR is activated by 2-alkyl-4-quinolones including the Pseudomonas quinolone signal (PQS; 2-heptyl-3-hydroxy-4(1H)-quinolone), its precursor 2-heptyl-4- hydroxyquinoline (HHQ) and their C9 congeners, 2-nonyl-3-hydroxy-4(1H)-quinolone (C9-PQS) and 2-nonyl-4-hydroxyquinoline (NHQ). These drive the autoinduction of AQ biosynthesis and the up-regulation of key virulence determinants as a function of bacterial population density. Consequently, PqsR constitutes a potential target for novel antibacterial agents which attenuate infection through the blockade of virulence. Here we present the crystal structures of the PqsR co-inducer binding domain (CBD) and a complex with the native agonist NHQ. We show that the structure of the PqsR CBD has an unusually large ligand-binding pocket in which a native AQ agonist is stabilized entirely by hydrophobic interactions. Through a ligand-based design strategy we synthesized and evaluated a series of 50 AQ and novel quinazolinone (QZN) analogues and measured the impact on AQ biosynthesis, virulence gene expression and biofilm development. The simple exchange of two isosteres (OH for NH2) switches a QZN agonist to an antagonist with a concomitant impact on the induction of bacterial virulence factor production. We also determined the complex crystal structure of a QZN antagonist bound to PqsR revealing a similar orientation in the ligand binding pocket to the native agonist NHQ. This structure represents the first description of an LTTR-antagonist complex. Overall these studies present novel insights into LTTR ligand binding and ligand-based drug design and provide a chemical scaffold for further anti-P. aeruginosa virulence drug development by targeting the AQ receptor PqsR

Investigations of the Mars Upper Atmosphere with ExoMars Trace Gas Orbiter

The Martian mesosphere and thermosphere, the region above about 60 km, is not the primary target of the ExoMars 2016 mission but its Trace Gas Orbiter (TGO) can explore it and address many interesting issues, either in-situ during the aerobraking period or remotely during the regular mission. In the aerobraking phase TGO peeks into thermospheric densities and temperatures, in a broad range of latitudes and during a long continuous period. TGO carries two instruments designed for the detection of trace species, NOMAD and ACS, which will use the solar occultation technique. Their regular sounding at the terminator up to very high altitudes in many different molecular bands will represent the first time that an extensive and precise dataset of densities and hopefully temperatures are obtained at those altitudes and local times on Mars. But there are additional capabilities in TGO for studying the upper atmosphere of Mars, and we review them briefly. Our simulations suggest that airglow emissions from the UV to the IR might be observed outside the terminator. If eventually confirmed from orbit, they would supply new information about atmospheric dynamics and variability. However, their optimal exploitation requires a special spacecraft pointing, currently not considered in the regular operations but feasible in our opinion. We discuss the synergy between the TGO instruments, specially the wide spectral range achieved by combining them. We also encourage coordinated operations with other Mars-observing missions capable of supplying simultaneous measurements of its upper atmosphere

Exploring the role of individual level and firm level dynamic capabilities in SMEs’ internationalization

This paper presents a multi-level model that examines the impact of dynamic capabilities on the internationalization of SMEs while taking into account the interactions among them. The purpose of the research is to understand the applicability of dynamic capabilities at the individual and the firm level to the SME internationalization process in developing country context and to assess to what extent a firm’s asset position and individual level dynamic capabilities influence the generation of firm level dynamic capabilities in SMEs. First, the dynamic capabilities theory was theoretically linked to the internationalization phenomenon. The relationships among firm-level dynamic capabilities, individual-level dynamic capabilities (owner specific dynamic capabilities), and internationalization were identified. The research framework and hypotheses were developed and empirically tested with 197 SMEs. The findings established that owner-specific dynamic capabilities have a positive influence on both firm dynamic capabilities and internationalization, and firm dynamic capabilities positively influence internationalization. It was also found that the market assets position measured as perceptual environmental dynamism positively influenced firm dynamic capabilities but structural and reputational asset positions of SMEs did not influence generation of firm dynamic capabilities. Moreover, firm dynamic capabilities had a mediation effect in the relationship between owner-specific dynamic capabilities and internationalization. Theoretically, this confirms the relevance of dynamic capability theory to internationalization and the possibility of integrating existing internationalization theories. Entrepreneurs, SME managers, and policy-makers could gain valuable insights on how entrepreneur and firm capabilities lead to better international prospects from this outcome

Participación en el Benchmark MATiS-H de la NEA/OCDE: Usos de códigos CFD aplicados a seguridad nuclear. Estudio de las rejillas espaciadoras en los elementos combustibles

Nuclear fuel bundles contain spacers essentially for mechanical stability and to influence the flow dynamic and heat transfer phenomena along the fuel rods. This work presents the analysis of the turbulence effects of a split-type and swirl-type spacer grid geometries on single-phase in a PWR (Pressurized Water Reactor) rod bundle. Various Computational Fluid Dynamics (CFD) calculations have been performed and the results validated with the experiments of the OECD/NEA-KAERI Rod Bundle CFD Benchmark Exercise on Turbulent Mixing in a Rod Bundle with Spacers at the MATiS-H facility. The aim of this Benchmark is to provide validated CFD analysis tools providing a firm basis for quantifying the CHF Margin reliably for normal operation and operational transients conditions and allowing eventually the use of CMFD Codes for predicting DNB under accidental conditions [1]. Simulation of turbulent phenomena downstream of the spacer grid presents high complexity issues. A wide range of length scales are present increasing the difficulty of defining in detail the transient nature of turbulent flow. Calculations were performed with the commercial code ANSYS R CFX R and CFD modelling using Large Eddy Simulation (LES) turbulence models by comparison with measurements to determine their suitability in the prediction of the turbulence phenomena. One of the most important aspects to be taken into account in order to properly simulate the flow downstream of the spacer grids is the use of a suitable turbulence model. Time-averaged values for all three velocity components, timeaveraged RMS values of the fluctuating component of all three velocity components in several cross-planes downstream of the spacer grid and circulation data in a selected sub-channel are in good agreement with the measured data. These results could be of great value for future studies of spacer grid including heat transfer from the rods and as a basis of spacer grid simplifications.Peña Monferrer, C.; Chiva Vicent, S.; Muñoz-Cobo González, JL.; Vela, E.; Pelayo, F. (2012). Participation in the NEA/OECD MATiS-H Benchmark exercise. Study of spacer grids in a rod bundle. Sociedad Nuclear Española. http://hdl.handle.net/10251/71522

Coherence loss in phase-referenced VLBI observations (

We report an erratum in an equation that models the relation of the limiting dynamic range to the angular distance between target and calibrator