We present a fast, accurate, robust, and flexible method of accelerating parameter estimation. This algorithm, called Pico, can compute the CMB power spectrum and matter transfer function, as well as ...any computationally expensive likelihoods, in a few milliseconds. By removing these bottlenecks from parameter estimation codes, Pico decreases their computational time by 1 or 2 orders of magnitude. Pico has several important properties. First, it is extremely fast and accurate over a large volume of parameter space. Furthermore, its accuracy can continue to be improved by using a larger training set. This method is generalizable to an arbitrary number of cosmological parameters and to any range of l-values in multipole space. Pico is approximately 3000 times faster than CAMB for flat models, and approximately 2000 times faster than the WMAP 3 yr likelihood code. In this paper, we demonstrate that using Pico to compute power spectra and likelihoods produces parameter posteriors that are very similar to those using CAMB and the official WMAP3 code, but in only a fraction of the time.
We use our most recent training set for the rico code to estimate the impact of recombination uncertainties on the posterior probability distributions which will be obtained from future cosmic ...microwave background experiments, and in particular the Planck satellite. Using a Monte Carlo Markov Chain (MCMC) analysis to sample the posterior distribution of the cosmological parameters, we find that Planck will have biases of −0.7, −0.3 and −0.4σ for nS, Ωbh2 and log(1010AS), respectively, in the minimal six-parameter Λ cold dark matter model, if the description of the recombination history given by rico is not used. The remaining parameters (e.g. τ or Ωdmh2) are not significantly affected. We also show that the cosmology dependence of the corrections to the recombination history modelled with rico has a negligible impact on the posterior distributions obtained for the case of the Planck satellite. In practice, this implies that the inclusion of additional corrections to existing recombination codes can be achieved using simple cosmology-independent ‘fudge functions’. Finally, we also investigated the impact of some recent improvements in the treatment of hydrogen recombination which are still not included in the current version of our training set for rico, by assuming that the cosmology dependence of those corrections can be neglected. In summary, with our current understanding of the complete recombination process, the expected biases in the cosmological parameters inferred from Planck might be as large as −2.3, −1.7 and −1σ for nS, Ωbh2 and log(1010AS), respectively, if all those corrections are not taken into account. We note that although the list of physical processes that could be of importance for Planck seems to be nearly complete, still some effort has to be put into the validation of the results obtained by the different groups. The new rico training set as well as the fudge functions used for this paper are publicly available on the rico webpage.
We present RICO, a code designed to compute the ionization fraction of the universe during the epoch of hydrogen and helium recombination with an unprecedented combination of speed and accuracy. This ...is accomplished by training the machine learning code PICO on the calculations of a multilevel cosmological recombination code which self-consistently includes several physical processes that were neglected previously. After training, RICO is used to fit the free electron fraction as a function of the cosmological parameters. While, for example, at low redshifts (z 900), much of the net change in the ionization fraction can be captured by lowering the hydrogen fudge factor in RECFAST by about 3%, RICO provides a means of effectively using the accurate ionization history of the full recombination code in the standard cosmological parameter estimation framework without the need to add new or refined fudge factors or functions to a simple recombination model. Within the new approach presented here, it is easy to update RICO whenever a more accurate full recombination code becomes available. Once trained, RICO computes the cosmological ionization history with negligible fitting error in ~10 ms, a speedup of at least 106 over the full recombination code that was used here. Also RICO is able to reproduce the ionization history of the full code to a level well below 0.1%, thereby ensuring that the theoretical power spectra of cosmic microwave background (CMB) fluctuations can be computed to sufficient accuracy and speed for analysis from upcoming CMB experiments like Planck. Furthermore, it will enable cross-checking different recombination codes across cosmological parameter space, a comparison that will be very important in order to assure the accurate interpretation of future CMB data.
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological ...conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche ...rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.
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•Lung metastases have elevated mTORC1 signaling compared with primary breast tumors•Blocking pyruvate uptake (Mct2 inhibition) impaired mTORC1 signaling in metastases•Silencing Phgdh impaired mTORC1 signaling in metastases, but not in primary tumors•Phgdh expression defined sensitivity to rapamycin only in metastases
Rinaldi et al. report that lung metastases and primary breast tumors use different nutrients and metabolic pathways to potentiate growth signaling. Mct2 inhibition or Phgdh silencing impaired mTORC1 signaling only in metastases. Consequently, Phgdh activity was required in lung metastases, but not in primary tumors, for sensitivity to rapamycin.
Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating ...endothelial cells (PECs) use fatty acid β-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1AΔEC mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1AΔEC mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1AΔEC mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.
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•QECs reprogram their metabolism to enhance redox homeostasis•QECs rely on fatty acid β-oxidation (FAO) to increase NADPH regeneration•Inhibition of FAO in QECs results in QEC dysfunction, which is rescued by acetate•Notch signaling upregulates transcription of CPT1A, a rate-controlling step in FAO
Kalucka et al. show that fatty acid β-oxidation in quiescent endothelial cells (QECs) is indispensable to maintain redox balance and prevent EC dysfunction. In contrast to proliferating ECs (PECs), QECs reprogram their metabolism to increase regeneration of NAPDH, which is then used by vasculoprotective (NADPH-consuming) enzymes for redox homeostasis.
Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report ...that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, impairs lymphatic development. LECs use fatty acid β-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid β-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.
Measuring intracellular metabolism has increasingly led to important insights in biomedical research. (13)C tracer analysis, although less information-rich than quantitative (13)C flux analysis that ...requires computational data integration, has been established as a time-efficient method to unravel relative pathway activities, qualitative changes in pathway contributions, and nutrient contributions. Here, we review selected key issues in interpreting (13)C metabolite labeling patterns, with the goal of drawing accurate conclusions from steady state and dynamic stable isotopic tracer experiments.
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