Infection Biomarkers Based on Metabolomics

Funding Information: Funding: This work was supported by the project grant DSAIPA/DS/0117/2020 supported by Fundação para a Ciência e a Tecnologia, Portugal; and by the project grant NeproMD/ISEL/2020 financed by Instituto Politécnico de Lisboa.Current infection biomarkers are highly limited since they have low capability to predict infection in the presence of confounding processes such as in non-infectious inflammatory processes, low capability to predict disease outcomes and have limited applications to guide and evaluate therapeutic regimes. Therefore, it is critical to discover and develop new and effective clinical infection biomarkers, especially applicable in patients at risk of developing severe illness and critically ill patients. Ideal biomarkers would effectively help physicians with better patient management, leading to a decrease of severe outcomes, personalize therapies, minimize antibiotics overuse and hospitalization time, and significantly improve patient survival. Metabolomics, by providing a direct insight into the functional metabolic outcome of an organism, presents a highly appealing strategy to discover these biomarkers. The present work reviews the desired main characteristics of infection biomarkers, the main metabolomics strategies to discover these biomarkers and the next steps for developing the area towards effective clinical biomarkers.publishersversionpublishe

The Impact of the Serum Extraction Protocol on Metabolomic Profiling Using UPLC-MS/MS and FTIR Spectroscopy

Funding Information: This research was funded by Fundação para a Ciência e a Tecnologia (FCT), Grants DSAIPA/DS/0117/2020 and RNEM-LISBOA-01-0145-FEDER-022125 (Portuguese Mass Spectrometry Network). The Centro de Química Estrutural is a Research Unit funded by FCT through projects UIDB/00100/2020 and UIDP/00100/2020. The Institute of Molecular Sciences is an Associate Laboratory funded by FCT through project LA/P/0056/2020. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.Biofluid metabolomics is a very appealing tool to increase the knowledge associated with pathophysiological mechanisms leading to better and new therapies and biomarkers for disease diagnosis and prognosis. However, due to the complex process of metabolome analysis, including the metabolome isolation method and the platform used to analyze it, there are diverse factors that affect metabolomics output. In the present work, the impact of two protocols to extract the serum metabolome, one using methanol and another using a mixture of methanol, acetonitrile, and water, was evaluated. The metabolome was analyzed by ultraperformance liquid chromatography associated with tandem mass spectrometry (UPLC-MS/MS), based on reverse-phase and hydrophobic chromatographic separations, and Fourier transform infrared (FTIR) spectroscopy. The two extraction protocols of the metabolome were compared over the analytical platforms (UPLC-MS/MS and FTIR spectroscopy) concerning the number of features, the type of features, common features, and the reproducibility of extraction replicas and analytical replicas. The ability of the extraction protocols to predict the survivability of critically ill patients hospitalized at an intensive care unit was also evaluated. The FTIR spectroscopy platform was compared to the UPLC-MS/MS platform and, despite not identifying metabolites and consequently not contributing as much as UPLC-MS/MS in terms of information concerning metabolic information, it enabled the comparison of the two extraction protocols as well as the development of very good predictive models of patient’s survivability, such as the UPLC-MS/MS platform. Furthermore, FTIR spectroscopy is based on much simpler procedures and is rapid, economic, and applicable in the high-throughput mode, i.e., enabling the simultaneous analysis of hundreds of samples in the microliter range in a couple of hours. Therefore, FTIR spectroscopy represents a very interesting complementary technique not only to optimize processes as the metabolome isolation but also for obtaining biomarkers such as those for disease prognosis.publishersversionpublishe

Simulations of core convection in rotating A-type stars: Differential rotation and overshooting

We present the results of 3--D simulations of core convection within A-type stars of 2 solar masses, at a range of rotation rates. We consider the inner 30% by radius of such stars, thereby encompassing the convective core and some of the surrounding radiative envelope. We utilize our anelastic spherical harmonic (ASH) code, which solves the compressible Navier-Stokes equations in the anelastic approximation, to examine highly nonlinear flows that can span multiple scale heights. The cores of these stars are found to rotate differentially, with central cylindrical regions of strikingly slow rotation achieved in our simulations of stars whose convective Rossby number (R_{oc}) is less than unity. Such differential rotation results from the redistribution of angular momentum by the nonlinear convection that strongly senses the overall rotation of the star. Penetrative convective motions extend into the overlying radiative zone, yielding a prolate shape (aligned with the rotation axis) to the central region in which nearly adiabatic stratification is achieved. This is further surrounded by a region of overshooting motions, the extent of which is greater at the equator than at the poles, yielding an overall spherical shape to the domain experiencing at least some convective mixing. We assess the overshooting achieved as the stability of the radiative exterior is varied, and the weak circulations that result in that exterior. The convective plumes serve to excite gravity waves in the radiative envelope, ranging from localized ripples of many scales to some remarkable global resonances.Comment: 48 pages, 16 figures, some color. Accepted to Astrophys. J. Color figures compressed with appreciable loss of quality; a PDF of the paper with better figures is available at http://lcd-www.colorado.edu/~brownim/core_convectsep24.pd

Turbulent Convection Under the Influence of Rotation: Sustaining a Strong Differential Rotation

The intense turbulence present in the solar convection zone is a major challenge to both theory and simulation as one tries to understand the origins of the striking differential rotation profile with radius and latitude that has been revealed by helioseismology. The differential rotation must be an essential element in the operation of the solar magnetic dynamo and its cycles of activity, yet there are many aspects of the interplay between convection, rotation and magnetic fields that are still unclear. We have here carried out a series of 3--D numerical simulations of turbulent convection within deep spherical shells using our anelastic spherical harmonic (ASH) code on massively parallel supercomputers. These studies of the global dynamics of the solar convection zone concentrate on how the differential rotation and meridional circulation are established. We have analyzed the transport of angular momentum in establishing such differential rotation, and clarified the roles played by Reynolds stresses and the meridional circulation in this process. We have found that the Reynolds stresses are crucial in transporting angular momentum toward the equator. The effects of baroclinicity (thermal wind) have been found to have a modest role in the resulting mean zonal flows. The simulations have produced differential rotation profiles within the bulk of the convection zone that make reasonable contact with ones inferred from helioseismic inversions, namely possessing a fast equator, an angular velocity difference of about 30% from equator to pole, and some constancy along radial lines at mid-latitudes.Comment: 25 pages, 14 very low resolution figures, shortened abstract, published by ApJ. High resolution/complete version can be found at http://lcd-www.colorado.edu/sabrun/index_cv.html then Scientific Publication

Magnetic fields and accretion flows on the classical T Tauri star V2129 Oph

From observations collected with the ESPaDOnS spectropolarimeter, we report the discovery of magnetic fields at the surface of the mildly accreting classical T Tauri star V2129 Oph. Zeeman signatures are detected, both in photospheric lines and in the emission lines formed at the base of the accretion funnels linking the disc to the protostar, and monitored over the whole rotation cycle of V2129 Oph. We observe that rotational modulation dominates the temporal variations of both unpolarized and circularly polarized line profiles. We reconstruct the large-scale magnetic topology at the surface of V2129 Oph from both sets of Zeeman signatures simultaneously. We find it to be rather complex, with a dominant octupolar component and a weak dipole of strengths 1.2 and 0.35 kG, respectively, both slightly tilted with respect to the rotation axis. The large-scale field is anchored in a pair of 2-kG unipolar radial field spots located at high latitudes and coinciding with cool dark polar spots at photospheric level. This large-scale field geometry is unusually complex compared to those of non-accreting cool active subgiants with moderate rotation rates. As an illustration, we provide a first attempt at modelling the magnetospheric topology and accretion funnels of V2129 Oph using field extrapolation. We find that the magnetosphere of V2129 Oph must extend to about 7R* to ensure that the footpoints of accretion funnels coincide with the high-latitude accretion spots on the stellar surface. It suggests that the stellar magnetic field succeeds in coupling to the accretion disc as far out as the corotation radius, and could possibly explain the slow rotation of V2129 Oph. The magnetospheric geometry we derive produces X-ray coronal fluxes typical of those observed in cTTSs.Comment: MNRAS, in press (18 pages, 17 figures

The formation of planetary disks and winds: an ultraviolet view

Planetary systems are angular momentum reservoirs generated during star formation. This accretion process produces very powerful engines able to drive the optical jets and the molecular outflows. A fraction of the engine energy is released into heating thus the temperature of the engine ranges from the 3000K of the inner disk material to the 10MK in the areas where magnetic reconnection occurs. There are important unsolved problems concerning the nature of the engine, its evolution and the impact of the engine in the chemical evolution of the inner disk. Of special relevance is the understanding of the shear layer between the stellar photosphere and the disk; this layer controls a significant fraction of the magnetic field building up and the subsequent dissipative processes ougth to be studied in the UV. This contribution focus on describing the connections between 1 Myr old suns and the Sun and the requirements for new UV instrumentation to address their evolution during this period. Two types of observations are shown to be needed: monitoring programmes and high resolution imaging down to, at least, milliarsecond scales.Comment: Accepted for publication in Astrophysics and Space Science 9 figure

PEARLS - A multicentre phase II/III trial of extended field radiotherapy for androgen sensitive prostate cancer patients with PSMA-avid pelvic and/or para-aortic lymph nodes at presentation.

PEARLS is a multi-stage randomised controlled trial for prostate cancer patients with pelvic and/or para-aortic PSMA-avid lymph node disease at presentation. The aim of the trial is to determine whether extending the radiotherapy field to cover the para-aortic lymph nodes (up to L1/L2 vertebral interspace) can improve outcomes for this patient group

Accretion Disks and Dynamos: Toward a Unified Mean Field Theory

Conversion of gravitational energy into radiation in accretion discs and the origin of large scale magnetic fields in astrophysical rotators have often been distinct topics of research. In semi-analytic work on both problems it has been useful to presume large scale symmetries, necessarily resulting in mean field theories. MHD turbulence makes the underlying systems locally asymmetric and nonlinear. Synergy between theory and simulations should aim for the development of practical mean field models that capture essential physics and can be used for observational modeling. Mean field dynamo (MFD) theory and alpha-viscosity accretion theory exemplify such ongoing pursuits. 21st century MFD theory has more nonlinear predictive power compared to 20th century MFD theory, whereas accretion theory is still in a 20th century state. In fact, insights from MFD theory are applicable to accretion theory and the two are artificially separated pieces of what should be a single theory. I discuss pieces of progress that provide clues toward a unified theory. A key concept is that large scale magnetic fields can be sustained via local or global magnetic helicity fluxes or via relaxation of small scale magnetic fluctuations, without the kinetic helicity driver of 20th century textbooks. These concepts may help explain the formation of large scale fields that supply non-local angular momentum transport via coronae and jets in a unified theory of accretion and dynamos. In diagnosing the role of helicities and helicity fluxes in disk simulations, each disk hemisphere should be studied separately to avoid being misled by cancelation that occurs as a result of reflection asymmetry. The fraction of helical field energy in disks is expected to be small compared to the total field in each hemisphere as a result of shear, but can still be essential for large scale dynamo action.Comment: For the Proceedings of the Third International Conference and Advanced School "Turbulent Mixing and Beyond," TMB-2011 held on 21 - 28 August 2011 at the Abdus Salam International Centre for Theoretical Physics, Trieste, http://users.ictp.it/~tmb/index2011.html Italy, To Appear in Physica Scripta (corrected small items to match version in print

Physics of Solar Prominences: II - Magnetic Structure and Dynamics

Observations and models of solar prominences are reviewed. We focus on non-eruptive prominences, and describe recent progress in four areas of prominence research: (1) magnetic structure deduced from observations and models, (2) the dynamics of prominence plasmas (formation and flows), (3) Magneto-hydrodynamic (MHD) waves in prominences and (4) the formation and large-scale patterns of the filament channels in which prominences are located. Finally, several outstanding issues in prominence research are discussed, along with observations and models required to resolve them.Comment: 75 pages, 31 pictures, review pape

Immune Biomarkers in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease in which molecular stratification is needed to improve clinical outcomes. The identification of predictive biomarkers can have a major impact on the care of these patients, but the availability of metastatic tissue samples for research in this setting is limited. OBJECTIVE: To study the prevalence of immune biomarkers of potential clinical utility to immunotherapy in mCRPC and to determine their association with overall survival (OS). DESIGN, SETTING, AND PARTICIPANTS: From 100 patients, mCRPC biopsies were assayed by whole exome sequencing, targeted next-generation sequencing, RNA sequencing, tumor mutational burden, T-cell-inflamed gene expression profile (TcellinfGEP) score (Nanostring), and immunohistochemistry for programmed cell death 1 ligand 1 (PD-L1), ataxia-telangiectasia mutated (ATM), phosphatase and tensin homolog (PTEN), SRY homology box 2 (SOX2), and the presence of neuroendocrine features. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The phi coefficient determined correlations between biomarkers of interest. OS was assessed using Kaplan-Meier curves and adjusted hazard ratios (aHRs) from Cox regression. RESULTS AND LIMITATIONS: PD-L1 and SOX2 protein expression was detected by immunohistochemistry (combined positive score ≥1 and >5% cells, respectively) in 24 (33%) and 27 (27%) mCRPC biopsies, respectively; 23 (26%) mCRPC biopsies had high TcellinfGEP scores (>-0.318). PD-L1 protein expression and TcellinfGEP scores were positively correlated (phi 0.63 [0.45; 0.76]). PD-L1 protein expression (aHR: 1.90 [1.05; 3.45]), high TcellinfGEP score (aHR: 1.86 [1.04; 3.31]), and SOX2 expression (aHR: 2.09 [1.20; 3.64]) were associated with worse OS. CONCLUSIONS: PD-L1, TcellinfGEP score, and SOX2 are prognostic of outcome from the mCRPC setting. If validated, predictive biomarker studies incorporating survival endpoints need to take these findings into consideration. PATIENT SUMMARY: This study presents an analysis of immune biomarkers in biopsies from patients with metastatic prostate cancer. We describe tumor alterations that predict prognosis that can impact future studies