An interface capturing method for liquid-gas flows at low-Mach number

Multiphase, compressible and viscous flows are of crucial importance in a wide range of scientific and engineering problems. Despite the large effort paid in the last decades to develop accurate and efficient numerical techniques to address this kind of problems, current models need to be further improved to address realistic applications. In this context, we propose a numerical approach to the simulation of multiphase, viscous flows where a compressible and an incompressible phase interact in the low-Mach number regime. In this frame, acoustics is neglected but large density variations of the compressible phase can be accounted for as well as heat transfer, convection and diffusion processes. The problem is addressed in a fully Eulerian framework exploiting a low-Mach number asymptotic expansion of the Navier-Stokes equations. A Volume of Fluid approach (VOF) is used to capture the liquid-gas interface, built on top of a massive parallel solver, second order accurate both in time and space. The second-order-pressure term is treated implicitly and the resulting pressure equation is solved with the eigenexpansion method employing a robust and novel formulation. We provide a detailed and complete description of the theoretical approach together with information about the numerical technique and implementation details. Results of benchmarking tests are provided for five different test cases

Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

PURPOSE: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. EXPERIMENTAL DESIGN: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. RESULTS: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. CONCLUSIONS: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men. TRANSLATIONAL RELEVANCE: It is well known that sex (i.e., the biological differences between men and women) and gender (i.e., behavioral differences associated with being male or female) are variables that affect immune responses to both foreign and selfantigens. Such sex- and gender-based dimorphism of immune system function, in turn reflects complex interactions between genes, hormones, the environment, and commensal microbiome composition. In our previous works, we showed that patients' sex is significantly associated with effectiveness of immune checkpoint inhibitors (ICIs) in patients with several solid tumors, including NSCLC. Here, we identified meaningful differences in molecular mechanisms that drive anticancer immune response as well as in immune evasion mechanisms exploited by NSCLCs arising in men and women. Importantly, we showed that all the findings reported, were not related to other variables potentially associated with sex such as patients' age, stage of disease, tumor histotype, and smoking status. The findings reported in this our work explain our previous clinical observations and can open this area to different immunotherapy strategies in males and females with NSCLC to further improve prognosis of both

Observation of the Shadowing of Cosmic Rays by the Moon using a Deep Underground Detector

Using data collected by the MACRO experiment during the years 1989-1996, we show evidence for the shadow of the moon in the underground cosmic ray flux with a significance of 3.6 sigma. This detection of the shadowing effect is the first by an underground detector. A maximum-likelihood analysis is used to determine that the angular resolution of the apparatus is 0.9+/-0.3 degrees. These results demonstrate MACRO's capabilities as a muon telescope by confirming its absolute pointing ability and quantifying its angular resolution.Comment: 14 pages, 8 figures Submitted to Phys. Rev.

Measurement of the atmospheric neutrino-induced upgoing muon flux using MACRO

We present a measurement of the flux of neutrino-induced upgoing muons (~100 GeV) using the MACRO detector. The ratio of the number of observed to expected events integrated over all zenith angles is 0.74 +/- 0.036 (stat) +/- 0.046(systematic) +/- 0.13 (theoretical). The observed zenith distribution for -1.0 < cos(theta) < -0.1 does not fit well with the no oscillation expectation, giving a maximum probability for chi^2 of 0.1%. The acceptance of the detector has been extensively studied using downgoing muons, independent analyses and Monte-Carlo simulations. The other systematic uncertainties cannot be the source of the discrepancies between the data and expectations. We have investigated whether the observed number of events and the shape of the zenith distribution can be explained by a neutrino oscillation hypothesis. Fitting either the flux or zenith distribution independently yields mixing parameters of sin^2 (2theta)=1.0 and delta m^2 of a few times 10^-3 eV^2. However, the observed zenith distribution does not fit well with any expectations giving a maximum probability for chi^2 of 5% for the best oscillation hypothesis, and the combined probability for the shape and number of events is 17%. We conclude that these data favor a neutrino oscillation hypothesis, but with unexplained structure in the zenith distribution not easily explained by either the statistics or systematics of the experiment.Comment: 7 pages (two-column) with 4 figure

Limits on dark matter WIMPs using upward-going muons in the MACRO detector

We perform an indirect search for Weakly Interacting Massive Particles (WIMPs) using the MACRO detector to look for neutrino-induced upward-going muons resulting from the annihilation of WIMPs trapped in the Sun and Earth. The search is conducted in various angular cones centered on the Sun and Earth to accommodate a range of WIMP masses. No significant excess over the background from atmospheric neutrinos is seen and limits are placed on the upward-going muon fluxes from Sun and Earth. These limits are used to constrain neutralino particle parameters from supersymmetric theory, including those suggested by recent results from DAMA/NaI.Comment: 14 pages, 7 figures, submitted to Phys. Rev.

Joint modelling of confounding factors and prominent genetic regulators provides increased accuracy in genetical genomics studies.

Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases.This work was funded by the European Regional Development Fund, European Union’s Horizon 2020 Research and Innovation Programme (BATCure grant No. 666918 to J.P.B., S.E.M., D.L.M., S.S., and T.R.M.; PANA grant No. 686009 to A.A.), Agencia Estatal de Investigación (PID2019-105699RB-I00/AEI/10.13039/501100011033 and RED2018‐102576‐T to J.P.B.; SAF2017-90794-REDT to A.A.), Instituto de Salud Carlos III (CB16/10/00282 to J.P.B.; PI18/00285; RD16/0019/0018 to A.A.), Junta de Castilla y León (CS/151P20 and Escalera de Excelencia CLU-2017-03 to J.P.B. and A.A.), Ayudas Equipos Investigación Biomedicina 2017 Fundación BBVA (to J.P.B.), and Fundación Ramón Areces (to J.P.B. and A.A.). SM benefits from MRC funding to the MRC Laboratory for Molecular Cell Biology University Unit at UCL (award code MC_U12266B) towards lab and office space. Part of this work was funded by Gero Discovery L.L.C. M.G.M. is an ISCIII-Sara Borrel contract recipient (CD18/00203)

Aberrant upregulation of glycolysis mediates CLN7 neuronal ceroid lipofuscinosis

Resumen del trabajo presentado en el 43rd Annual Meeting of the Spanish Society of Biochemistry & Molecular Biology, celebrado en Barcelona, del 19 al 22 de julio de 2021CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in the autophagy-lysosomal pathway causes accumulation of structurally and bioenergetically impaired neuronal mi- tochondria. In vivo genetic approach revealed elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolysis activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFK- FB3, a glycolytic-promoting enzyme normally unstable in healthy neurons. Pharmacological inhibition of PFKFB3 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectified key disease hallmarks. Thus, aberrant upregulation of neuronal glycolysis contributes to CLN7 patho-genesis and targeting PFKFB3 may alleviate this and other lysosomal storage diseasesThis work was funded by Agencia Estatal de Investigación (PID2019-105699RB-I00).Peer reviewe

The IXPE View of GRB 221009A

We present the IXPE observation of GRB 221009A, which includes upper limits on the linear polarization degree of both prompt and afterglow emission in the soft X-ray energy band. GRB 221009A is an exceptionally bright gamma-ray burst (GRB) that reached Earth on 2022 October 9 after traveling through the dust of the Milky Way. The Imaging X-ray Polarimetry Explorer (IXPE) pointed at GRB 221009A on October 11 to observe, for the first time, the 2–8 keV X-ray polarization of a GRB afterglow. We set an upper limit to the polarization degree of the afterglow emission of 13.8% at a 99% confidence level. This result provides constraints on the jet opening angle and the viewing angle of the GRB, or alternatively, other properties of the emission region. Additionally, IXPE captured halo-rings of dust-scattered photons that are echoes of the GRB prompt emission. The 99% confidence level upper limit to the prompt polarization degree depends on the background model assumption, and it ranges between ∼55% and ∼82%. This single IXPE pointing provides both the first assessment of X-ray polarization of a GRB afterglow and the first GRB study with polarization observations of both the prompt and afterglow phases