Given genomic variation data from multiple individuals, computing the likelihood of complex population genetic models is often infeasible. To circumvent this problem, we introduce a novel ...likelihood-free inference framework by applying deep learning, a powerful modern technique in machine learning. Deep learning makes use of multilayer neural networks to learn a feature-based function from the input (e.g., hundreds of correlated summary statistics of data) to the output (e.g., population genetic parameters of interest). We demonstrate that deep learning can be effectively employed for population genetic inference and learning informative features of data. As a concrete application, we focus on the challenging problem of jointly inferring natural selection and demography (in the form of a population size change history). Our method is able to separate the global nature of demography from the local nature of selection, without sequential steps for these two factors. Studying demography and selection jointly is motivated by Drosophila, where pervasive selection confounds demographic analysis. We apply our method to 197 African Drosophila melanogaster genomes from Zambia to infer both their overall demography, and regions of their genome under selection. We find many regions of the genome that have experienced hard sweeps, and fewer under selection on standing variation (soft sweep) or balancing selection. Interestingly, we find that soft sweeps and balancing selection occur more frequently closer to the centromere of each chromosome. In addition, our demographic inference suggests that previously estimated bottlenecks for African Drosophila melanogaster are too extreme.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In prerecombination resolutions of the Hubble tension, such as early dark energy, new physics before recombination shifts the values of relevant cosmological parameters so that the models can fit ...with cosmic microwave background and baryon acoustic oscillations observations as well as LambdaCDM does. In this paper, we clarify how the parameter shifts are related with δH0, particularly we find the shift of primordial scalar spectral index scales as δns ≃ ... by performing the Monte Carlo Markov chain analysis with the Planck 2018 + BAO + Pantheon + R 19 + Keck Array/BICEP dataset. A novel point of our result is that if the current H0 measured locally is correct, complete resolution of the Hubble tension seems to be pointing to a scale invariant Harrison-Zeldovich spectrum, i.e., ns = 1 for H0 ∼ 73 km / s / Mpc. (ProQuest: ... denotes formula omitted.).
Previous studies have shown that translation elongation is regulated by multiple factors, but the observed heterogeneity remains only partially explained. To dissect quantitatively the different ...determinants of elongation speed, we use probabilistic modeling to estimate initiation and local elongation rates from ribosome profiling data. This model-based approach allows us to quantify the extent of interference between ribosomes on the same transcript. We show that neither interference nor the distribution of slow codons is sufficient to explain the observed heterogeneity. Instead, we find that electrostatic interactions between the ribosomal exit tunnel and specific parts of the nascent polypeptide govern the elongation rate variation as the polypeptide makes its initial pass through the tunnel. Once the N-terminus has escaped the tunnel, the hydropathy of the nascent polypeptide within the ribosome plays a major role in modulating the speed. We show that our results are consistent with the biophysical properties of the tunnel.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A
bstract
The nonsingular bounce models usually suffer from the ghost or gradient instabilities, as has been proved recently. In this paper, we propose a covariant effective theory for stable ...nonsingular bounce, which has the quadratic order of the second order derivative of the field
ϕ
but the background set only by
P
(
ϕ, X
). With it, we explicitly construct a fully stable nonsingular bounce model for the ekpyrotic scenario.
It has recently been demonstrated that inference methods based on genealogical processes with recombination can uncover past population history in unprecedented detail. However, these methods scale ...poorly with sample size, limiting resolution in the recent past, and they require phased genomes, which contain switch errors that can catastrophically distort the inferred history. Here we present SMC++, a new statistical tool capable of analyzing orders of magnitude more samples than existing methods while requiring only unphased genomes (its results are independent of phasing). SMC++ can jointly infer population size histories and split times in diverged populations, and it employs a novel spline regularization scheme that greatly reduces estimation error. We apply SMC++ to analyze sequence data from over a thousand human genomes in Africa and Eurasia, hundreds of genomes from a Drosophila melanogaster population in Africa, and tens of genomes from zebra finch and long-tailed finch populations in Australia.
Present-day temperature T0 of cosmic microwave background has been precisely measured by the FIRAS experiment. We identify that the early dark energy (EDE) (non-negligible around matter-radiation ...equality) scenario can remain compatible with the FIRAS result, while lifting the Hubble constant H0. We perform Monte Carlo Markov chain analysis to confirm our observations. We also present an α-attractor anti–de Sitter (AdS) model of EDE, in which the AdS depth is consistently varied in the Monte Carlo Markov chain analysis. We found that our datasets weakly hinted the existence of an AdS phase near recombination with H0 ∼ 73 km/s / Mpc at 1σ region in the best-fit model.
Requiring the existence of a unitary, causal and local UV-completion places a set of positivity bounds on the corresponding effective field theories (EFTs). We discuss the obstructions and ...possibility in applying the positivity bound to cosmology, in particular the EFT of cosmological perturbations. Taking a
c
T
=
1
beyond-Horndeski EFT as an illustrative example, we derive such bounds, which incorporate the cosmological correction of order
H
2
/
Λ
2
,
Λ
being the cutoff scale. The derived bounds are applied to slow-roll inflation with beyond Horndeski operators. It is found that the cosmological positivity bounds may be either stronger or weaker than their flat space counterpart.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar ...metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.
In the studies on pre-recombination early dark energy (EDE), the evolution of Universe after recombination is usually regarded as ΛCDM-like, which corresponds that the equation of state of dark ...energy responsible for current accelerated expansion is w=−1. However, in realistic models, w might be evolving. We consider the parametrizations of w with respect to the redshift z in Axion-like EDE and AdS-EDE models, respectively. We performed the Monte Carlo Markov chain analysis with recent cosmological data, and found that the bestfit w(z) is compatible with w0=−1,wa=0 (the cosmological constant) and the evolution of w is only marginally favored, which so has little effect on lifting the bestfit value of H0.
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