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Abstract Background TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 activity – which may occur due to alterations in trans – from gene expression patterns. Several such alterations that phenocopy p53 loss are known, however additional ones may exist, but their identity and prevalence among human tumors are not well characterized. Results We perform a large-scale statistical analysis on transcriptomes of ~ 7,000 tumors and ~ 1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines, respectively, phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations. While some of these cases are explained by amplifications in the known phenocopying genes MDM2, MDM4 and PPM1D, many are not. An association analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional common TP53-loss phenocopying gene, USP28. Deletions in USP28 are associated with a TP53 functional impairment in 2.9–7.6% of breast, bladder, lung, liver and stomach tumors, and have comparable effect size to MDM4 amplifications. Additionally, in the known copy number alteration (CNA) segment harboring MDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost the TP53 functional inactivation effect of MDM2. An analysis of cancer cell line drug screens using phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and various genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a drug activity modifying factor in precision medicine. As a resource, we provide the drug-genetic marker associations that differ depending on TP53 functional status. Conclusions Human tumors that do not bear obvious TP53 genetic alterations but that phenocopy p53 activity loss are common, and the USP28 gene deletions are one likely cause.

The structure of magnetic fields in galaxies remains poorly constrained, despite the importance of magnetism in the evolution of galaxies. Radio synchrotron and far-infrared (FIR) polarization and polarimetric observations are the best methods to measure galactic scale properties of magnetic fields in galaxies beyond the Milky Way. We use synthetic polarimetric observations of a simulated galaxy to identify and quantify the regions, scales, and interstellar medium (ISM) phases probed at FIR and radio wavelengths. Our studied suite of magnetohydrodynamical cosmological zoom-in simulations features high-resolutions (10 pc full-cell size) and multiple magnetization models. Our synthetic observations have a striking resemblance to those of observed galaxies. We find that the total and polarized radio emission extends to approximately double the altitude above the galactic disk (half-intensity disk thickness of h _I radio ∼ h _PI radio = 0.23 ± 0.03 kpc) relative to the total FIR and polarized emission that are concentrated in the disk midplane ( h _I FIR ∼ h _PI FIR = 0.11 ± 0.01 kpc). Radio emission traces magnetic fields at scales of ≳300 pc, whereas FIR emission probes magnetic fields at the smallest scales of our simulations. These scales are comparable to our spatial resolution and well below the spatial resolution (

Resumen: Desde Lalonde sabemos que los determinantes que más influyen en la Salud de la población son el estilo de vida, la genética y el entorno. La sanidad representa solo el 10% y es el determinante que más recursos consume. Está demostrado que un enfoque salutogénico centrado en los determinantes sociales de la salud y el apoyo de políticas públicas para mejorar el entorno, son más eficientes a largo plazo que la medicina centrada en los hospitales, la tecnología y la superespecialización. La Atención Primaria (AP) que tiene un enfoque centrado en la persona y las familias con una visión comunitaria, es el nivel idóneo para proveer atención sanitaria, y para influir en los estilos de vida. Sin embargo no se invierte en AP. En este artículo revisamos los condicionantes socioeconómicos y políticos que influyen de manera global en la falta de interés en el desarrollo de la AP. Abstract: At Lalonde we know that the determinants that most influence the health of the population are lifestyle, genetics and the environment. Health represents only 10% and is the determinant that consumes the most resources. It has been shown that a salutogenic approach focused on the social determinants of health and the support of public policies to improve the environment are more efficient in the long term than medicine focused on hospitals, technology and super-specialization. Primary Care (PC) that has an approach centered on the person and families with a community vision, is the ideal level to provide health care, and to influence lifestyles. However it is not invested in PC. In this article we review the socioeconomic and political factors that globally influence the lack of interest in the development of PC.

Aims. The true nature of primordial magnetic fields (PMFs) and their role in the formation of galaxies remains elusive. To shed light on these unknowns, we investigated their impact by varying two sets of properties: (i) accounting for the effect of PMFs on the initial matter power spectrum and (ii) accounting for their magneto-hydrodynamical effects on the formation of galaxies. By comparing both, we can determine the dominant agent in shaping galaxy evolution. Methods. We used the magneto-hydrodynamics code RAMSES to generate multiple new zoom-in simulations for eight different host halos of dwarf galaxies across a wide luminosity range of 103 − 106 L⊙. These halos were selected from a ΛCDM cosmological box, tracking their evolution down to redshift z = 0. We explored a variety of primordial magnetic field (comoving) strengths of Bλ ranging from 0.05 to 0.50 nG. Results. We find that magnetic fields in the interstellar medium not only modify star formation processes in dwarf spheroidal galaxies, but these fields also entirely prevent the formation of stars in less compact, ultra-faint galaxies with halo masses and stellar masses below, respectively, ∼2.5 × 109 and 3 × 106 M⊙. At high redshifts, the impact of PMFs on host halos of dwarf galaxies through the modification of the matter power spectrum is more dominant than the influence of magneto-hydrodynamics in shaping their gaseous structure. Through the amplification of small perturbations ranging in mass from 107 to 109 M⊙ in the ΛCDM+PMFs matter power spectrum, primordial fields expedite the formation of the first dark matter halos, leading to an earlier onset and a higher star formation rate at redshifts of z > 9. We investigated the evolution of various energy components and demonstrated that magnetic fields with an initial strength of Bλ ≥ 0.05 nG exhibit a strong growth of magnetic energy, accompanied by a saturation phase that begins soon after the growth phase. These trends persist consistently, regardless of the initial conditions or whether it is the classical ΛCDM model or ΛCDM modified by PMFs. Lastly, we investigated the impact of PMFs on the present-time observable properties of dwarf galaxies, namely: the half light radius, V-band luminosity, mean metallicity, and velocity dispersion profile. We find that PMFs with moderate strengths of Bλ ≤ 0.10 nG show an impressive agreement with the scaling relations of the observed Local Group dwarfs. However, stronger fields lead to larger sizes and higher velocity dispersions. [ABSTRACT FROM AUTHOR]

Mergers are thought to be a fundamental channel for galaxy growth, perturbing the gas dynamics and the magnetic fields ( B -fields) in the interstellar medium (ISM). However, the mechanisms that amplify and dissipate B -fields during a merger remain unclear. We characterize the morphology of the ordered B -fields in the multiphase ISM of the closest merger of two spiral galaxies, the Antennae galaxies. We compare the inferred B -fields using 154 μ m thermal dust and 11 cm radio synchrotron emission polarimetric observations. We find that the 154 μ m B -fields are more ordered across the Antennae galaxies than the 11 cm B -fields. The turbulent-to-ordered 154 μ m B -field increases at the galaxy cores and star-forming regions. The relic spiral arm has an ordered spiral 154 μ m B -field, while the 11 cm B -field is radial. The 154 μ m B -field may be dominated by turbulent dynamos with high ^12 CO(1–0) velocity dispersion driven by star-forming regions, while the 11 cm B -field is cospatial with high H i velocity dispersion driven by galaxy interaction. This result shows the dissociation between the warm gas mainly disturbed by the merger, and the dense gas still following the dynamics of the relic spiral arm. We find a ∼8.9 kpc scale ordered B -field connecting the two galaxies. The base of the tidal tail is cospatial with the H i and ^12 CO(1–0) emission and has compressed and/or sheared 154 μ m and 11 cm B -fields driven by the merger. We suggest that amplified B -fields, with respect to the rest of the system and other spiral galaxies, may be supporting the gas flow between both galaxies and the tidal tail.

We present the analysis of the magnetic field ( B -field) structure of galaxies measured with far-infrared (FIR) and radio (3 and 6 cm) polarimetric observations. We use the first data release of the Survey of extragALactic magnetiSm with SOFIA of 14 nearby ( $\lt 20$ Mpc) galaxies with resolved ( $5^{\prime\prime} \mbox{--}18^{\prime\prime} ;$ 90 pc–1 kpc) imaging polarimetric observations using SOFIA/HAWC+ from 53 to 214 μ m. We compute the magnetic pitch-angle ( ${{\rm{\Psi }}}_{B}$ ) profiles as a function of the galactocentric radius. We introduce a new magnetic alignment parameter ( ζ ) to estimate the disordered-to-ordered ratio of spiral B -fields. We find FIR and radio wavelengths to not generally trace the same B -field morphology in galaxies. The ${{\rm{\Psi }}}_{B}$ profiles tend to be more ordered across all galactocentric radii in radio ( ${\zeta }_{6\mathrm{cm}}\,=\,0.93\pm 0.03$ ) than in FIR ( ${\zeta }_{154\mu {\rm{m}}}=0.84\pm 0.14$ ). For spiral galaxies, FIR B -fields are 2%–75% more turbulent than the radio B -fields. For starburst galaxies, we find that FIR polarization is a better tracer of the B -fields along the galactic outflows than radio polarization. Our results suggest that the B -fields associated with dense, dusty, turbulent star-forming regions (those traced at FIR) are less ordered than warmer, less dense regions (those traced at radio) of the interstellar medium. The FIR B -fields seem to be more sensitive to the activity of the star-forming regions and molecular clouds within a vertical height of a few hundred parsecs in the disk of spiral galaxies than the radio B -fields.

Lyα emission is an exceptionally informative tracer of the life cycle of evolving galaxies and the escape of ionizing photons. However, theoretical studies of Lyα emission are often limited by insufficient numerical resolution, incomplete sets of physical models, and poor line-of-sight (LOS) statistics. To overcome such limitations, we utilize here the novel pandora suite of high-resolution dwarf galaxy simulations that include a comprehensive set of state-of-the-art physical models for ionizing radiation, magnetic fields, supernova feedback, and cosmic rays. We post-process the simulations with the radiative transfer code rascas to generate synthetic observations and compare to the observed properties of Lyα emitters. Our simulated Lyα haloes are more extended than the spatial region from which the intrinsic emission emanates, and our spatially resolved maps of spectral parameters of the Lyα emission are very sensitive to the underlying spatial distribution and kinematics of neutral hydrogen. Lyα and LyC emissions display strongly varying signatures along different LOS depending on how each LOS intersects low-density channels generated by stellar feedback. Comparing galaxies simulated with different physics, we find the Lyα signatures to exhibit systematic offsets determined by the different levels of feedback strength and the clumpiness of the neutral gas. Despite this variance, and regardless of the different physics included in each model, we find universal correlations between Lyα observables and LyC escape fraction, demonstrating a robust connection between Lyα and LyC emission. Lyα observations from a large sample of dwarf galaxies should thus give strong constraints on their stellar feedback-regulated LyC escape and confirm their important role for the re-ionization of the Universe. [ABSTRACT FROM AUTHOR]

During the last decade, cosmological simulations have managed to reproduce realistic and morphologically diverse galaxies, spanning the Hubble sequence. Central to this success was a phenomenological calibration of the few included feedback processes, while glossing over higher complexity baryonic physics. This approach diminishes the predictive power of such simulations, preventing to further our understanding of galaxy formation. To tackle this fundamental issue, we investigate the impact of cosmic rays (CRs) and magnetic fields on the interstellar medium and the launching of outflows in a cosmological zoom-in simulation of a Milky Way-like galaxy. We find that including CRs decreases the stellar mass of the galaxy by a factor of 10 at high redshift and ∼4 at cosmic noon, leading to a stellar mass to halo mass ratio in good agreement with abundance matching models. Such decrease is caused by two effects: (i) a reduction of cold, high-density, star-forming gas, and (ii) a larger fraction of supernova (SN) events exploding at lower densities, where they have a higher impact. SN-injected CRs produce enhanced, multiphase galactic outflows, which are accelerated by CR pressure gradients in the circumgalactic medium of the galaxy. While the mass budget of these outflows is dominated by the warm ionized gas, warm neutral and cold gas phases contribute significantly at high redshifts. Importantly, our work shows that future JWST observations of galaxies and their multiphase outflows across cosmic time have the ability to constrain the role of CRs in regulating star formation. [ABSTRACT FROM AUTHOR]

Observational cosmology in the next decade will rely on probes of the distribution of matter in the redshift range between 0

We present the analysis of the magnetic field (B -field) structure of galaxies measured with far-infrared (FIR) and radio (3 and 6 cm) polarimetric observations. We use the first data release of the Survey of extragALactic magnetiSm with SOFIA of 14 nearby ( < 20 Mpc) galaxies with resolved ( 5 ″ – 18 ″ ; 90 pc–1 kpc) imaging polarimetric observations using SOFIA/HAWC+ from 53 to 214 μ m. We compute the magnetic pitch-angle ( Ψ B ) profiles as a function of the galactocentric radius. We introduce a new magnetic alignment parameter (ζ) to estimate the disordered-to-ordered ratio of spiral B -fields. We find FIR and radio wavelengths to not generally trace the same B -field morphology in galaxies. The Ψ B profiles tend to be more ordered across all galactocentric radii in radio ( ζ 6 cm = 0.93 ± 0.03) than in FIR ( ζ 154 μ m = 0.84 ± 0.14). For spiral galaxies, FIR B -fields are 2%–75% more turbulent than the radio B -fields. For starburst galaxies, we find that FIR polarization is a better tracer of the B -fields along the galactic outflows than radio polarization. Our results suggest that the B -fields associated with dense, dusty, turbulent star-forming regions (those traced at FIR) are less ordered than warmer, less dense regions (those traced at radio) of the interstellar medium. The FIR B -fields seem to be more sensitive to the activity of the star-forming regions and molecular clouds within a vertical height of a few hundred parsecs in the disk of spiral galaxies than the radio B -fields. [ABSTRACT FROM AUTHOR]

Aims Exercise echocardiography (ExE) may evaluate left ventricular (LV) systolic and diastolic function. We aimed to assess the value of diastolic parameters at exercise [early LV inflow velocity to early tissue Doppler annulus velocity (E / e ′)] in patients with normal or abnormal resting diastolic function (DF) referred for a clinically indicated ExE. Methods and results LV systolic and DF according to ASE/EACVI guidelines and mitral regurgitation (MR) were evaluated at rest in 772 patients (age 67 ± 12 years) with preserved LV ejection fraction (LVEF ≥ 50%). We assessed regional/global LV systolic function at peak exercise, while MR and E / e ′ where evaluated in the immediate post-exercise period. Abnormal ExE was defined as ischaemia or fixed wall motion abnormalities, and raised E / e ′ values as >15 at rest and at exercise (e ′ at the septal level). Patients were grouped as complaining or not of dyspnoea. Events were overall mortality, myocardial infarction, admission for unstable angina or cardiac failure, and coronary revascularization. DF was abnormal at rest in 221 patients (29%) and indeterminate in 77 (10%), with similar percentages in patients with and without dyspnoea. Exercise E / e ′ >15 was found in 37% of patients with abnormal DF, 21% with indeterminate DF, and 6% with normal DF (P < 0.001). Patients with abnormal ExE had more often abnormal resting DF (39% vs. 25%, P = 0.001) and exercise E / e ′ >15 (25% vs. 13%, P < 0.001) than those with normal ExE. During a median follow-up of 1.68 years, there were 132 events. Independent predictors included peak exercise LVEF [hazard ratio (HR) = 0.93, 95% confidence interval (CI) = 0.91–0.94, P < 0.001], and exercise E / e ′ (HR= 1.04, 95% CI = 1.01–1.07, P = 0.01). Neither resting E / e ′ values nor resting abnormal DF by ASE/EACVI guidelines, were independent predictors. Annualized event-rates were 43.2% in patients with (+) ExE plus (+) exercise E / e ′, 23.8% in those with (+) ExE and (−) exercise E / e ′, 7.9% in (−) ExE and (+) exercise E / e ′, and 3.6% with both variables normal. Conclusions The results of diastolic dysfunction at rest and at exercise were similar between patients with or without dyspnoea referred for ExE, but they were associated with abnormal ExE. Exercise E / e ′ reclassified 21% of patients with indeterminate DF and further predicted outcome on top of ExE results. [ABSTRACT FROM AUTHOR]

Enshrouded in several well-known controversies, dwarf galaxies have been extensively studied to learn about the underlying cosmology, notwithstanding that physical processes regulating their properties are poorly understood. To shed light on these processes, we introduce the Pandora suite of 17 high-resolution (3.5 parsec half-cell side) dwarf galaxy formation cosmological simulations. Commencing with magneto-thermo-turbulent star formation and mechanical supernova (SN) feedback, we gradually increase the complexity of physics incorporated, ultimately leading to our full-physics models combining magnetism, on-the-fly radiative transfer and the corresponding stellar photoheating, and SN-accelerated cosmic rays. We investigate multiple combinations of these processes, comparing them with observations to constrain what are the main mechanisms determining dwarf galaxy properties. We find hydrodynamical 'SN feedback-only' simulations struggle to produce realistic dwarf galaxies, leading either to overquenched or too centrally concentrated, dispersion-dominated systems when compared to observed field dwarfs. Accounting for radiation with cosmic rays results in extended and rotationally supported systems. Spatially 'distributed' feedback leads to realistic stellar and H  i masses, galaxy sizes, and integrated kinematics. Furthermore, resolved kinematic maps of our full-physics models predict kinematically distinct clumps and kinematic misalignments of stars, H  i , and H  ii after star formation events. Episodic star formation combined with its associated feedback induces more core-like dark matter central profiles, which our 'SN feedback-only' models struggle to achieve. Our results demonstrate the complexity of physical processes required to capture realistic dwarf galaxy properties, making tangible predictions for integral field unit surveys, radio synchrotron emission, and for galaxy and multiphase interstellar medium properties that JWST will probe. [ABSTRACT FROM AUTHOR]