Fast and Credible Likelihood-Free Cosmology with Truncated Marginal Neural Ratio Estimation

Sampling-based inference techniques are central to modern cosmological data analysis; these methods, however, scale poorly with dimensionality and typically require approximate or intractable likelihoods. In this paper we describe how Truncated Marginal Neural Ratio Estimation (TMNRE) (a new approach in so-called simulation-based inference) naturally evades these issues, improving the $(i)$ efficiency, $(ii)$ scalability, and $(iii)$ trustworthiness of the inferred posteriors. Using measurements of the Cosmic Microwave Background (CMB), we show that TMNRE can achieve converged posteriors using orders of magnitude fewer simulator calls than conventional Markov Chain Monte Carlo (MCMC) methods. Remarkably, the required number of samples is effectively independent of the number of nuisance parameters. In addition, a property called \emph{local amortization} allows the performance of rigorous statistical consistency checks that are not accessible to sampling-based methods. TMNRE promises to become a powerful tool for cosmological data analysis, particularly in the context of extended cosmologies, where the timescale required for conventional sampling-based inference methods to converge can greatly exceed that of simple cosmological models such as $\Lambda$CDM. To perform these computations, we use an implementation of TMNRE via the open-source code \texttt{swyft}.Comment: v2: accepted journal version. v1: 37 pages, 13 figures. \texttt{swyft} is available at https://github.com/undark-lab/swyft, and demonstration code for cosmological examples is available at https://github.com/acole1221/swyft-CM

Accounting for heterogeneous invasion rates reveals management impacts on the spatial expansion of an invasive species

Success of large-scale control programs for established invasive species is challenging to evaluate because of spatial variability in expansion rates, management techniques, and the strength of management intensity. For a well-established invasive species in the spreading phase of invasion, a useful metric of impact is the magnitude by which control slows the rate of spatial spread. The prevention of spatial spreading likely results in substantial benefits in terms of ecosystem or economic damage that is prevented by an expanding invasive species. To understand how local management actions could impact the spatial spread of an established invasive species, we analyzed distribution and management data for feral swine across contiguous United States using occupancy analysis. We quantified changes in the rate of spatial expansion of feral swine and its relationship to local management actions. We found that after 4 yr of enhanced control, invasion probability decreased by 8% on average relative to pre-program rates. This decrease was as high as 15% on average in states with low-density populations of feral swine. The amount of decrease in invasion rate was attributed to removal intensity in neighboring counties and depended on the extent of neighboring counties with feral swine (spatial heterogeneity in local invasion pressure). Although we did not find a significant overall increase in the probability of elimination, increased elimination probability tended to occur in regions with low invasion pressure. Accounting for spatial heterogeneity in invasion pressure was important for quantifying management impacts (i.e., the relationship between management intensity and spatial spreading processes) because management impacts changed depending on the strength of invasion pressure from neighboring counties. Predicting reduction in spatial spread of an invasive species is an important first step in valuation of overall damage reduction for invasive species control programs by providing estimates of where a species may be, and thus which natural and agricultural resources would be affected, if the control program had not been operating. For minimizing losses from spatial expansion of an invasive species, our framework can be used for adaptive resource prioritization to areas where spatial expansion and underlying damage potential are concurrently highest

Accounting for heterogeneous invasion rates reveals management impacts on the spatial expansion of an invasive species

Success of large-scale control programs for established invasive species is challenging to evaluate because of spatial variability in expansion rates, management techniques, and the strength of management intensity. For a well-established invasive species in the spreading phase of invasion, a useful metric of impact is the magnitude by which control slows the rate of spatial spread. The prevention of spatial spreading likely results in substantial benefits in terms of ecosystem or economic damage that is prevented by an expanding invasive species. To understand how local management actions could impact the spatial spread of an established invasive species, we analyzed distribution and management data for feral swine across contiguous United States using occupancy analysis. We quantified changes in the rate of spatial expansion of feral swine and its relationship to local management actions. We found that after 4 yr of enhanced control, invasion probability decreased by 8% on average relative to pre-program rates. This decrease was as high as 15% on average in states with low-density populations of feral swine. The amount of decrease in invasion rate was attributed to removal intensity in neighboring counties and depended on the extent of neighboring counties with feral swine (spatial heterogeneity in local invasion pressure). Although we did not find a significant overall increase in the probability of elimination, increased elimination probability tended to occur in regions with low invasion pressure. Accounting for spatial heterogeneity in invasion pressure was important for quantifying management impacts (i.e., the relationship between management intensity and spatial spreading processes) because management impacts changed depending on the strength of invasion pressure from neighboring counties. Predicting reduction in spatial spread of an invasive species is an important first step in valuation of overall damage reduction for invasive species control programs by providing estimates of where a species may be, and thus which natural and agricultural resources would be affected, if the control program had not been operating. For minimizing losses from spatial expansion of an invasive species, our framework can be used for adaptive resource prioritization to areas where spatial expansion and underlying damage potential are concurrently highest

Cyclic di-GMP-dependent Signaling Pathways in the Pathogenic Firmicute Listeria Monocytogenes

We characterized key components and major targets of the c-di-GMP signaling pathways in the foodborne pathogen Listeria monocytogenes, identified a new c-di-GMP-inducible exopolysaccharide responsible for motility inhibition, cell aggregation, and enhanced tolerance to disinfectants and desiccation, and provided first insights into the role of c-di-GMP signaling in listerial virulence. Genome-wide genetic and biochemical analyses of c-di-GMP signaling pathways revealed that L. monocytogenes has three GGDEF domain proteins, DgcA (Lmo1911), DgcB (Lmo1912) and DgcC (Lmo2174), that possess diguanylate cyclase activity, and three EAL domain proteins, PdeB (Lmo0131), PdeC (Lmo1914) and PdeD (Lmo0111), that possess c-di-GMP phosphodiesterase activity. Deletion of all phosphodiesterase genes (ΔpdeB/C/D) or expression of a heterologous diguanylate cyclase stimulated production of a previously unknown exopolysaccharide. The synthesis of this exopolysaccharide was attributed to the pssA-E (lmo0527-0531) gene cluster. The last gene of the cluster encodes the fourth listerial GGDEF domain protein, PssE, that functions as an I-site c-di-GMP receptor essential for exopolysaccharide synthesis. The c-di-GMP-inducible exopolysaccharide causes cell aggregation in minimal medium and impairs bacterial migration in semi-solid agar, however, it does not promote biofilm formation on abiotic surfaces. The exopolysaccharide also greatly enhances bacterial tolerance to commonly used disinfectants as well as desiccation, which may contribute to survival of L. monocytogenes on contaminated food products and in food-processing facilities. The exopolysaccharide and another, as yet unknown c-di-GMP-dependent target, drastically decrease listerial invasiveness in enterocytes in vitro, and lower pathogen load in the liver and gallbladder of mice infected via an oral route, which suggests that elevated c-di-GMP levels play an overall negative role in listerial virulence

Cyclic di-GMP-Dependent Signaling Pathways in the Pathogenic Firmicute \u3cem\u3eListeria monocytogenes\u3c/em\u3e

We characterized key components and major targets of the c-di-GMP signaling pathways in the foodborne pathogen Listeria monocytogenes, identified a new c-di-GMP-inducible exopolysaccharide responsible for motility inhibition, cell aggregation, and enhanced tolerance to disinfectants and desiccation, and provided first insights into the role of c-di-GMP signaling in listerial virulence. Genome-wide genetic and biochemical analyses of c-di-GMP signaling pathways revealed that L. monocytogenes has three GGDEF domain proteins, DgcA (Lmo1911), DgcB (Lmo1912) and DgcC (Lmo2174), that possess diguanylate cyclase activity, and three EAL domain proteins, PdeB (Lmo0131), PdeC (Lmo1914) and PdeD (Lmo0111), that possess c-di-GMP phosphodiesterase activity. Deletion of all phosphodiesterase genes (ΔpdeB/C/D) or expression of a heterologous diguanylate cyclase stimulated production of a previously unknown exopolysaccharide. The synthesis of this exopolysaccharide was attributed to the pssA-E (lmo0527-0531) gene cluster. The last gene of the cluster encodes the fourth listerial GGDEF domain protein, PssE, that functions as an I-site c-di-GMP receptor essential for exopolysaccharide synthesis. The c-di-GMP-inducible exopolysaccharide causes cell aggregation in minimal medium and impairs bacterial migration in semi-solid agar, however, it does not promote biofilm formation on abiotic surfaces. The exopolysaccharide also greatly enhances bacterial tolerance to commonly used disinfectants as well as desiccation, which may contribute to survival of L. monocytogenes on contaminated food products and in food-processing facilities. The exopolysaccharide and another, as yet unknown c-di-GMP-dependent target, drastically decrease listerial invasiveness in enterocytes in vitro, and lower pathogen load in the liver and gallbladder of mice infected via an oral route, which suggests that elevated c-di-GMP levels play an overall negative role in listerial virulence

X-ray, Optical, and Radio Observations of the Type II Supernovae 1999em and 1998S

Observations of the Type II-P (plateau) Supernova (SN) 1999em and Type IIn (narrow emission line) SN 1998S have enabled estimation of the profile of the SN ejecta, the structure of the circumstellar medium (CSM) established by the pre-SN stellar wind, and the nature of the shock interaction. SN 1999em is the first Type II-P detected at both X-ray and radio wavelengths. The Chandra X-ray data indicate non-radiative interaction of SN ejecta with a power-law density profile (rho \propto r^{-n} with n ~ 7) with a pre-SN wind with a low mass-loss rate of ~2 \times 10^{-6} M_sun/yr for a wind velocity of 10 km/sec, in agreement with radio mass-loss rate estimates. The Chandra data show an unexpected, temporary rise in the 0.4--2.0 keV X-ray flux at ~100 days after explosion. SN 1998S, at an age of >3 years, is still bright in X-rays and is increasing in flux density at cm radio wavelengths. Spectral fits to the Chandra data show that many heavy elements (Ne, Al, Si, S, Ar, and Fe) are overabundant with respect to solar values. We compare the observed elemental abundances and abundance ratios to theoretical calculations and find that our data are consistent with a progenitor mass of approximately 15-20 M_sun if the heavy element ejecta are radially mixed out to a high velocity. If the X-ray emission is from the reverse shock wave region, the supernova density profile must be moderately flat at a velocity ~10^4 km/sec, the shock front is non-radiative at the time of the observations, and the mass-loss rate is 1-2 \times 10^{-4} M_sun/yr for a pre-supernova wind velocity of 10 km/sec. This result is also supported by modeling of the radio emission which implies that SN 1998S is surrounded by a clumpy or filamentary CSM established by a high mass-loss rate, ~2 \times 10^{-4} M_sun/yr, from the pre-supernova star.Comment: 14 pages, 10 figures, accepted by ApJ, includes new data (one new obs. each of SN 1999em and SN 1998S), expanded discussion of spectral fit

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease

25-Hydroxyvitamin D Depletion Does Not Exacerbate MPTP-Induced Dopamine Neuron Damage in Mice

Recent clinical evidence supports a link between 25-hydroxyvitamin D insufficiency (serum 25-hydroxyvitamin D [25(OH)D] levels <30 ng/mL) and Parkinson’s disease. To investigate the effect of 25(OH)D depletion on neuronal susceptibility to toxic insult, we induced a state of 25(OH)D deficiency in mice and then challenged them with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found there was no significant difference between control and 25(OH)D-deficient animals in striatal dopamine levels or dopamine transporter and tyrosine hydroxylase expression after lesioning with MPTP. Additionally, we found no difference in tyrosine hydroxylase expression in the substantia nigra pars compacta. Our data suggest that reducing 25(OH)D serum levels in mice has no effect on the vulnerability of nigral dopaminergic neurons in vivo in this model system of parkinsonism