Various computational approaches have been developed for estimating the relative abundance of different cell types in the tumor microenvironment (TME) using bulk tumor RNA data. However, a ...comprehensive comparison across diverse datasets that objectively evaluates the performance of these approaches has not been conducted. Here, we benchmarked seven widely used tools and gene sets and introduced Consensus
, a method that integrates gene sets from all the other methods for relative TME cell estimation of 18 cell types. We collected a comprehensive benchmark dataset consisting of pan-cancer data (DNA-derived purity, leukocyte methylation, and hematoxylin and eosin-derived lymphocyte counts) and cell-specific benchmark datasets (peripheral blood cells and tumor tissues). Although none of the methods outperformed others in every benchmark, Consensus
ranked top three in all cancer-related benchmarks and was the best performing tool overall. We provide a Web resource to interactively explore the benchmark results and an objective evaluation to help researchers select the most robust and accurate method to further investigate the role of the TME in cancer (www.consensusTME.org). SIGNIFICANCE: This work shows an independent and comprehensive benchmarking of recently developed and widely used tumor microenvironment cell estimation methods based on bulk expression data and integrates the tools into a consensus approach.
Based on new and published cosmic-ray exposure chronologies, we show that glacier extent in the tropical Andes and the north Atlantic regions (TANAR) varied in-phase on millennial timescales during ...the Holocene, distinct from other regions. Glaciers experienced an early Holocene maximum extent, followed by a strong mid-Holocene retreat and a re-advance in the late Holocene. We further explore the potential forcing of TANAR glacier variations using transient climate simulations. Since the Atlantic Meridional Overturning Circulation (AMOC) evolution is poorly represented in these transient simulations, we develop a semi-empirical model to estimate the "AMOC-corrected" temperature and precipitation footprint at regional scales. We show that variations in the AMOC strength during the Holocene are consistent with the observed glacier changes. Our findings highlight the need to better constrain past AMOC behavior, as it may be an important driver of TANAR glacier variations during the Holocene, superimposed on other forcing mechanisms.
Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation. Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate ...kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine. Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. This reduction in PKM2 activity shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation.
Both environmental and economic factors have driven the development of recycling routes for the increasing amount of composite waste generated. This paper presents a new paradigm to fully recycle ...epoxy‐based carbon fiber reinforced polymer (CFRP) composites. After immersing the composite in ethylene glycol (EG) and increasing the temperature, the epoxy matrix can be dissolved as the EG molecules participate in bond exchange reactions (BERs) within the covalent adaptable network (CAN), effectively breaking the long polymer chains into small segments. The clean carbon fibers can be then reclaimed with the same dimensions and mechanical properties as those of fresh ones. Both the dissolution rate and the minimum amount of EG required to fully dissolve the CAN are experimentally determined. Further heating the dissolved solution leads to repolymerization of the epoxy matrix, so a new generation of composite can be fabricated by using the recycled fiber and epoxy; in this way a closed‐loop near 100% recycling paradigm is realized. In addition, epoxy composites with surface damage are shown to be fully repaired. Both the recycled and the repaired composites exhibit the same level of mechanical properties as fresh materials.
A new method to fully recycle the carbon fiber reinforced thermoset composites is developed. After immersing the composite in solvent, the polymer matrix can be dissolved and clean carbon fibers are reclaimed; both, matrix material and carbon fibres, can be recycled and reused for the same purpose. The developed method can also be used to repair composite with surface damage.
Straight beams, rods and trusses are common elements in structural and mechanical engineering, but recent advances in additive manufacturing now also enable efficient freeform fabrication of curved, ...deformable beams and beam structures, such as microstructures, metamaterials and conformal lattices. To exploit this new design freedom for applications with nonlinear mechanical behavior, we introduce an isogeometric method for shape optimization of curved 3D beams and beam structures. The geometrically exact Cosserat rod theory is used to model nonlinear 3D beams subject to large deformations and rotations. The initial and current geometry are parameterized in terms of NURBS curves describing the beam centerline and an isogeometric collocation approach is used to discretize the strong form of the balance equations. Then, a nonlinear optimization problem is formulated in order to optimize the positions of the control points of the NURBS curve that describes the beam centerline, i.e., the geometry or shape of the beam. To solve the design problem using gradient-based algorithms, we introduce semi-analytical, inconsistent analytical and fully analytical approaches for calculation of design sensitivities. The methods are numerically validated and their performance is investigated, before the applicability and versatility of our 3D beam shape optimization method is illustrated in various numerical applications, including optimization of an auxetic 3D metamaterial.
•Shape of curved, freeform, nonlinear 3D beams is optimized in terms of centerline curve.•NURBS-based integration of isogeometric collocation for nonlinear analysis and optimization.•Control points of centerline curves serve directly as design variables for optimization.•Incomplete analytical and fully analytical sensitivities are derived for gradient-based optimization.•Numerical validation and application to optimization of an auxetic metamaterial.
The direct measurement of topological invariants in both engineered and naturally occurring quantum materials is a key step in classifying quantum phases of matter. Here, we motivate a toolbox based ...on time-dependent quantum walks as a method to digitally simulate single-particle topological band structures. Using a superconducting qubit dispersively coupled to a microwave cavity, we implement two classes of split-step quantum walks and directly measure the topological invariant (winding number) associated with each. The measurement relies upon interference between two components of a cavity Schrödinger cat state and highlights a novel refocusing technique, which allows for the direct implementation of a digital version of Bloch oscillations. As the walk is performed in phase space, our scheme can be extended to higher synthetic dimensions by adding additional microwave cavities, whereby superconducting circuit-based simulations can probe topological phases ranging from the quantum-spin Hall effect to the Hopf insulator.
Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants. The first exposure to PFAS occurs in utero, after birth it continues via breast milk, food intake, environment, and ...consumer products that contain these chemicals. Our aim was to identify determinants of PFAS concentrations in sensitive population subgroups– pregnant women and newborns.
Nine European birth cohorts provided exposure data on PFAS in pregnant women (INMA-Gipuzkoa, Sabadell, Valencia, ELFE and MoBa; total N = 5897) or newborns (3xG study, FLEHS 2, FLEHS 3 and PRENATAL; total N = 940). PFOS, PFOA, PFHxS and PFNA concentrations were measured in maternal or cord blood, depending on the cohort (FLEHS 2 measured only PFOS and PFOA). PFAS concentrations were analysed according to maternal characteristics (age, BMI, parity, previous breastfeeding, smoking, and food consumption during pregnancy) and parental educational level. The association between potential determinants and PFAS concentrations was evaluated using multiple linear regression models.
We observed significant variations in PFAS concentrations among cohorts. Higher PFAS concentrations were associated with higher maternal age, primipara birth, and educational level, both for maternal blood and cord blood. Higher PFAS concentrations in maternal blood were associated with higher consumption of fish and seafood, meat, offal and eggs. In cord blood, higher PFHxS concentrations were associated with daily meat consumption and higher PFNA with offal consumption. Daily milk and dairy consumption were associated with lower concentrations of PFAS in both, pregnant women and newborns.
High detection rates of the four most abundant PFAS demonstrate ubiquitous exposure of sensitive populations, which is of concern. This study identified several determinants of PFAS exposure in pregnant women and newborns, including dietary factors, and these findings can be used for proposing measures to reduce PFAS exposure, particularly from dietary sources.
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•High detection rates of PFAS were observed in the blood of pregnant women and newborns.•Higher educational level of father was associated with higher PFAS in cord blood.•Dietary factors were associated with PFAS concentrations in pregnant women.•Daily milk and dairy consumption was associated with lower PFAS in both populations.
In textbook expositions of the equity-premium, riskfree-rate and equity-volatility puzzles, agents are sure of the economy's structure while growth rates are normally distributed. But because of ...parameter uncertainty the thin-tailed normal distribution conditioned on realized data becomes a thick-tailed Student-t distribution, which changes the entire nature of what is considered "puzzling" by reversing every inequality discrepancy needing to be explained. This paper shows that Bayesian updating of unknown structural parameters inevitably adds a permanent tail-thickening effect to posterior expectations. The expected-utility ramifications of this for asset pricing are strong, work against the puzzles, and are very sensitive to subjective prior beliefs-even with asymptotically infinite data.
Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used ...whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
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