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Understanding the molecular mechanisms of congenital diseases is challenging due to their occurrence within specific developmental stages. Esophageal malformations are examples of such conditions, characterized by abnormalities in the development of esophagus during embryogenesis. These developmental malformations encompass a range of anomalies, including esophageal atresia, and tracheoesophageal fistula. Here, we investigated the preferential expression of 29 genes that are implicated in such malformations and their immediate interactome (a total of 67 genes). We conducted our analyses across several single-cell atlases of embryonic development, encompassing approximately 150,000 cells from the mouse foregut, 180,000 cells from human embryos, and 500,000 cells from 24 human organs. Our study, spanning diverse mesodermal and endodermal cell populations and early developmental stages, shows that the genes associated with esophageal malformations show their highest cell-type specific expression in lateral plate mesoderm cells and at the developmental stage of E8.75–E9.0 days. In human embryos, these genes show a significant cell-type specific expression among subpopulations of epithelial cells, fibroblasts and progenitor cells including basal cells. Notably, members of the forkhead-box family of transcription factors, namely FOXF1 , FOXC1 , and FOXD1 , as well as the SRY-box transcription factor, SOX2 , demonstrate the most significant preferential expression in both mouse and human embryos. Overall, our findings provide insights into the temporal and cellular contexts contributing to esophageal malformations.

Background: The Norwegian forest resource map (SR16) maps forest attributes by combining national forest inventory (NFI), airborne laser scanning (ALS) and other remotely sensed data. While the ALS data were acquired over a time interval of 10 years using various sensors and settings, the NFI data are continuously collected. Aims of this study were to analyze the effects of stratification on models linking remotely sensed and field data, and assess the accuracy overall and at the ALS project level. Materials and methods: The model dataset consisted of 9203 NFI field plots and data from 367 ALS projects, covering 17 Mha and 2/3 of the productive forest in Norway. Mixed-effects regression models were used to account for differences among ALS projects. Two types of stratification were used to fit models: 1) stratification by the three main tree species groups spruce, pine and deciduous resulted in species-specific models that can utilize a satellite-based species map for improving predictions, and 2) stratification by species and maturity class resulted in stratum-specific models that can be used in forest management inventories where each stand regularly is visually stratified accordingly. Stratified models were compared to general models that were fit without stratifying the data. Results: The species-specific models had relative root-mean-squared errors (RMSEs) of 35%, 34%, 31%, and 12% for volume, aboveground biomass, basal area, and Lorey's height, respectively. These RMSEs were 2-7 percentage points (pp) smaller than those of general models. When validating using predicted species, RMSEs were 0-4 pp. smaller than those of general models. Models stratified by main species and maturity class further improved RMSEs compared to species-specific models by up to 1.8 pp. Using mixed-effects models over ordinary least squares models resulted in a decrease of RMSE for timber volume of 1.0-3.9 pp., depending on the main tree species. RMSEs for timber volume ranged between 19%-59% among individual ALS projects. Conclusions: The stratification by tree species considerably improved models of forest structural variables. A further stratification by maturity class improved these models only moderately. The accuracy of the models utilized in SR16 were within the range reported from other ALS-based forest inventories, but local variations are apparent.

Population games are games with a finite set of available strategies and an infinite number of players, in which the reward for choosing a given strategy is a function of the distribution of players over strategies. The paper shows that, in a certain class of maxmin optimization problems, it is possible to associate a population game to a given maxmin problem in such a way that solutions to the optimization problem are found from Nash equilibria of the associated game. Iterative solution methods for maxmin optimization problems can then be derived from systems of differential equations whose trajectories are known to converge to Nash equilibria. In particular, we use a discrete-time version of the celebrated replicator equation of evolutionary game theory, also known in machine learning as the exponential multiplicative weights algorithm. The resulting algorithm can be viewed as a generalization of the Iteratively Reweighted Least Squares (IRLS) method, which is well known in numerical analysis as a useful technique for solving Chebyshev function approximation problems on a finite grid. Examples are provided to show the use of the generalized IRLS method in collective investment and in decision making under model uncertainty.

In a risk exchange, participants trade a privately owned risk for a share in a pool. If participants agree on a valuation rule, it can be decided whether or not, according to the given rule, these trades take place at equal value. If equality of values holds for all participants, then the exchange is said to be “financially fair”. It has been shown by Bühlmann and Jewell (1979) that, under mild assumptions, the constraint of financial fairness singles out a unique solution among the set of all Pareto efficient risk exchanges. In this paper, we find that an analogous statement is true if we limit ourselves to linear exchanges. Conditions are provided for existence and uniqueness of linear sharing rules that are both financially fair and Pareto efficient among all linear sharing rules. The performance of the linear rule is compared to that of the general (nonlinear) rule in a number of specific cases.

Gollier proposed in 2008 a model for the analysis of pension schemes that is helpful to focus attention on the impact of intergenerational risk sharing and on the role of the participation constraint. He uses the model to analyze the relative attractiveness of a collective scheme with respect to schemes that may be implemented by individuals for themselves. The analysis makes use of an assumption concerning the ownership rights of investment returns realized by generations that are between career start and retirement at the time of the transition from an individual to a collective system. The present paper investigates the consequences of adopting an alternative assumption. In a calibration exercise, the increase of the effective rate of return obtained by switching from an existing ‘autarky’ scheme to an infinite-horizon ‘collective’ scheme is found to be 8 basis points, as opposed to 72 basis points as reported by Gollier. Additionally, the effects are considered of changes in the specification of agents' preferences, aiming to express the specific nature of retirement income provision in the second pillar. The Black–Scholes assumptions are used to model the economic environment, so that many results can be obtained in closed form.

This paper connects discrete optimal transport to a certain class of multi-objective optimization problems. In both settings, the decision variables can be organized into a matrix. In the multi-objective problem, the notion of Pareto efficiency is defined in terms of the objectives together with nonnegativity constraints and with equality constraints that are specified in terms of column sums. A second set of equality constraints, defined in terms of row sums, is used to single out particular points in the Pareto-efficient set which are referred to as “balanced solutions.” Examples from several fields are shown in which this solution concept appears naturally. Balanced solutions are shown to be in one-to-one correspondence with solutions of optimal transport problems. As an example of the use of alternative interpretations, the computation of solutions via regularization is discussed.

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5′-ppp-dsRNA), and profile the transcriptomes at three time points. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis -regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS loci and show a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli in modifying genetic predisposition to disease. Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.

For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls. We complement this analysis by systematically mining the literature space for supporting evidence. In addition to providing supporting evidence for well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we also find sex steroid hormones, plasma lipids, and telomere length as determinants of cancer risk. A number of the molecular factors we identify may prove to be potential biomarkers. Our analysis, which highlights aetiological similarities and differences in common cancers, should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app to visualise findings. Mendelian randomisation can identify potential risk factors from large populations. Here, the authors analyse 3000 traits across multiple cancer types to search for potential risk factors and molecular biomarkers.

There is an urgent need to quantify anthropogenic influence on forest carbon stocks. Using satellite-based radar imagery for such purposes has been challenged by the apparent loss of signal sensitivity to changes in forest aboveground volume (AGV) above a certain ‘saturation’ point. The causes of saturation are debated and often inadequately addressed, posing a major limitation to mapping AGV with the latest radar satellites. Using ground- and lidar-measurements across La Rioja province (Spain) and Denmark, we investigate how various properties of forest structure (average stem height, size and number density; proportion of canopy and understory cover) simultaneously influence radar backscatter. It is found that increases in backscatter due to changes in some properties (e.g. increasing stem sizes) are often compensated by equal magnitude decreases caused by other properties (e.g. decreasing stem numbers and increasing heights), contributing to the apparent saturation of the AGV-backscatter trend. Thus, knowledge of the impact of management practices and disturbances on forest structure may allow the use of radar imagery for forest biomass estimates beyond commonly reported saturation points.

Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases. Looking at genes that are differentially responsive to pathogens depending on the genetic background may help in the identification of therapeutic targets in personalized medicine. Here, using challenge of monocytes with three pathogens the authors identified eQTL that are shared between pathogens and loci that are pathogen specific.