FIRE-2 Simulations: Physics versus Numerics in Galaxy Formation

The Feedback In Realistic Environments (FIRE) project explores feedback in cosmological galaxy formation simulations. Previous FIRE simulations used an identical source code (“FIRE-1”) for consistency. Motivated by the development of more accurate numerics – including hydrodynamic solvers, gravitational softening, and supernova coupling algorithms – and exploration of new physics (e.g. magnetic fields), we introduce “FIRE-2”, an updated numerical implementation of FIRE physics for the GIZMO code. We run a suite of simulations and compare against FIRE-1: overall, FIRE-2 improvements do not qualitatively change galaxy-scale properties. We pursue an extensive study of numerics versus physics. Details of the star-formation algorithm, cooling physics, and chemistry have weak effects, provided that we include metal-line cooling and star formation occurs at higher-than-mean densities. We present new resolution criteria for high-resolution galaxy simulations. Most galaxy-scale properties are robust to numerics we test, provided: (1) Toomre masses are resolved; (2) feedback coupling ensures conservation, and (3) individual supernovae are time-resolved. Stellar masses and profiles are most robust to resolution, followed by metal abundances and morphologies, followed by properties of winds and circum-galactic media (CGM). Central (∼kpc) mass concentrations in massive (>L*) galaxies are sensitive to numerics (via trapping/recycling of winds in hot halos). Multiple feedback mechanisms play key roles: supernovae regulate stellar masses/winds; stellar mass-loss fuels late star formation; radiative feedback suppresses accretion onto dwarfs and instantaneous star formation in disks. We provide all initial conditions and numerical algorithms used

Swirls of FIRE: spatially resolved gas velocity dispersions and star formation rates in FIRE-2 disc environments

We study the spatially resolved (sub-kpc) gas velocity dispersion (σ)–star formation rate (SFR) relation in the FIRE-2 (Feedback in Realistic Environments) cosmological simulations. We specifically focus on Milky Way-mass disc galaxies at late times (z ≈ 0). In agreement with observations, we find a relatively flat relationship, with σ ≈ 15–30 km s⁻¹ in neutral gas across 3 dex in SFRs. We show that higher dense gas fractions (ratios of dense gas to neutral gas) and SFRs are correlated at constant σ. Similarly, lower gas fractions (ratios of gas to stellar mass) are correlated with higher σ at constant SFR. The limits of the σ–Σ_(SFR) relation correspond to the onset of strong outflows. We see evidence of ‘on-off’ cycles of star formation in the simulations, corresponding to feedback injection time-scales of 10–100 Myr, where SFRs oscillate about equilibrium SFR predictions. Finally, SFRs and velocity dispersions in the simulations agree well with feedback-regulated and marginally stable gas disc (Toomre’s Q = 1) model predictions, and the simulation data effectively rule out models assuming that gas turns into stars at (low) constant efficiency (i.e. 1 per cent per free-fall time). And although the simulation data do not entirely exclude gas accretion/gravitationally powered turbulence as a driver of σ, it appears to be subdominant to stellar feedback in the simulated galaxy discs at z ≈ 0

Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma

Mutations in the ALK tyrosine kinase receptor gene represent important therapeutic targets in neuroblastoma, yet their clinical translation has been challenging. The ALKF1174L mutation is sensitive to the ALK inhibitor crizotinib only at high doses and mediates acquired resistance to crizotinib in ALK-translocated cancers. We have shown that the combination of crizotinib and an inhibitor of downstream signaling induces a favorable response in transgenic mice bearing ALKF1174L/MYCN-positive neuroblastoma. Here, we investigated the molecular basis of this effect and assessed whether a similar strategy would be effective in ALK-mutated tumors lacking MYCN overexpression. We show that in ALK-mutated, MYCN-amplified neuroblastoma cells, crizotinib alone does not affect mTORC1 activity as indicated by persistent RPS6 phosphorylation. Combined treatment with crizotinib and an ATP-competitive mTOR inhibitor abrogated RPS6 phosphorylation, leading to reduced tumor growth and prolonged survival in ALKF1174L/MYCN-positive models compared to single agent treatment. By contrast, this combination, while inducing mTORC1 downregulation, caused reciprocal upregulation of PI3K activity in ALK-mutated cells expressing wild-type MYCN. Here, an inhibitor with potency against both mTOR and PI3K was more effective in promoting cytotoxicity when combined with crizotinib. Our findings should enable a more precise selection of molecularly targeted agents for patients with ALK-mutated tumors

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo

Initial conditions for hybrid inflation

In hybrid inflation models, typically only a tiny fraction of possible initial conditions give rise to successful inflation, even if one assumes spatial homogeneity. We analyze some possible solutions to this initial conditions problem, namely assisted hybrid inflation and hybrid inflation on the brane. While the former is successful in achieving the onset of inflation for a wide range of initial conditions, it lacks sound physical motivation at present. On the other hand, in the context of the presently much discussed brane cosmology, extra friction terms appear in the Friedmann equation which solve this initial conditions problem in a natural way.Comment: 6 pages RevTeX file with four figures incorporated (uses RevTeX and epsf). Updates to match accepted versio

FIRE-2 Simulations: Physics versus Numerics in Galaxy Formation

The Feedback In Realistic Environments (FIRE) project explores feedback in cosmological galaxy formation simulations. Previous FIRE simulations used an identical source code (“FIRE-1”) for consistency. Motivated by the development of more accurate numerics – including hydrodynamic solvers, gravitational softening, and supernova coupling algorithms – and exploration of new physics (e.g. magnetic fields), we introduce “FIRE-2”, an updated numerical implementation of FIRE physics for the GIZMO code. We run a suite of simulations and compare against FIRE-1: overall, FIRE-2 improvements do not qualitatively change galaxy-scale properties. We pursue an extensive study of numerics versus physics. Details of the star-formation algorithm, cooling physics, and chemistry have weak effects, provided that we include metal-line cooling and star formation occurs at higher-than-mean densities. We present new resolution criteria for high-resolution galaxy simulations. Most galaxy-scale properties are robust to numerics we test, provided: (1) Toomre masses are resolved; (2) feedback coupling ensures conservation, and (3) individual supernovae are time-resolved. Stellar masses and profiles are most robust to resolution, followed by metal abundances and morphologies, followed by properties of winds and circum-galactic media (CGM). Central (∼kpc) mass concentrations in massive (>L*) galaxies are sensitive to numerics (via trapping/recycling of winds in hot halos). Multiple feedback mechanisms play key roles: supernovae regulate stellar masses/winds; stellar mass-loss fuels late star formation; radiative feedback suppresses accretion onto dwarfs and instantaneous star formation in disks. We provide all initial conditions and numerical algorithms used

Swirls of FIRE: spatially resolved gas velocity dispersions and star formation rates in FIRE-2 disc environments

We study the spatially resolved (sub-kpc) gas velocity dispersion (sigma)-star formation rate (SFR) relation in the FIRE-2 (Feedback in Realistic Environments) cosmological simulations. We specifically focus on Milky Way-mass disc galaxies at late times (z approximate to 0). In agreement with observations, we find a relatively flat relationship, with sigma approximate to N 15-30 km s(-1) in neutral gas across 3 dex in SFRs. We show that higher dense gas fractions (ratios of dense gas to neutral gas) and SFRs arc correlated at constant sigma. Similarly, lower gas fractions (ratios of gas to stellar mass) are correlated with higher sigma at constant SFR. The limits of the sigma-Sigma(SFR) relation correspond to the onset of strong outflows. We see evidence of 'on-off' cycles of star formation in the simulations, corresponding to feedback injection time-scales of 10-100 Myr, where SFRs oscillate about equilibrium SFR predictions. Finally, SFRs and velocity dispersions in the simulations agree well with feedback-regulated and marginally stable gas disc (Toomre's Q = 1) model predictions, and the simulation data effectively rule out models assuming that gas turns into stars at (low) constant efficiency (i.e. 1 per cent per free-fall time). And although the simulation data do not entirely exclude gas accretion/gravitationally powered turbulence as a driver of sigma, it appears to be subdominant to stellar feedback in the simulated galaxy discs at z approximate to 0.MEO is grateful for the encouragement of his late father, SRO, in studying astrophysics, and is supported by the National Science Foundation Graduate Research Fellowship under grant no. 1144469. The authors are grateful to the referee for their comments and providing useful suggestions. The Flatiron Institute is supported by the Simons Foundation. Support for AMM is provided by NASA through Hubble Fellowship grant #HST-HF2-51377 awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555. Support for PFH was provided by an Alfred P. Sloan Foundation Research Fellowship, NASA ATP grant NNX14AH35G, and NSF Collaborative Research grant #1411920 and CAREER grant #1455342. CAFG was supported by NSF through grants AST-1517491, AST-1715216, and CAREER award AST-1652522, by 0:funding-source 3:href="http://dx.doi.o rg/10.13039/100000104" NASA /0:funding-source through grant 17-ATP17-0067, and by a Cottrell Scholar Award from the Research Corporation for Science Advancement. DK acknowledges support from the NSF Grant AST-1412153 and Cottrell Scholar Award from the Research Corporation for Science Advancement. EQ was supported by NASA ATP grant 12-ATP12-0183, a Simons Investigator award from the Simons Foundation, and the David and Lucile Packard Foundation. AW received support from NASA, through ATP grant 80NSSC18K1097 and HST grants GO-14734 and AR-15057 from STScI, the Heising-Simons Foundation, and a Hellman Foundation Fellowship

A mouse informatics platform for phenotypic and translational discovery

The International Mouse Phenotyping Consortium (IMPC) is providing the world’s first functional catalogue of a mammalian genome by characterising a knockout mouse strain for every gene. A robust and highly structured informatics platform has been developed to systematically collate, analyse and disseminate the data produced by the IMPC. As the first phase of the project, in which 5000 new knockout strains are being broadly phenotyped, nears completion, the informatics platform is extending and adapting to support the increasing volume and complexity of the data produced as well as addressing a large volume of users and emerging user groups. An intuitive interface helps researchers explore IMPC data by giving overviews and the ability to find and visualise data that support a phenotype assertion. Dedicated disease pages allow researchers to find new mouse models of human diseases, and novel viewers provide high-resolution images of embryonic and adult dysmorphologies. With each monthly release, the informatics platform will continue to evolve to support the increased data volume and to maintain its position as the primary route of access to IMPC data and as an invaluable resource for clinical and non-clinical researchers

A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas

Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1α. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1α activity in tumors