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Soccer is constantly changing regarding the demands of the new generation. At its best, young players develop outstanding technical and tactical skills as well as a wealth of competition experience. In addition to targeted training, maintaining motivation is one of the biggest challenges facing youth coaches. One possible way is to build their confidence while having fun. As a new game form, 3 vs. 3 unites the main events of the soccer game, challenges young players in a versatile manner, and promotes joy. In the present study, 23 games played in the new and 16 games played in the established competitive styles (7 vs. 7 and 6 vs. 6) were compared and analyzed regarding the variables passing, dribbling, shooting, and scoring. MANOVA revealed a significant effect for the factor game form: F(4,33) = 8.974, p 2 = 0.521. Additionally, post-hoc comparisons (using Sidak correction) indicated a significantly higher number for the occurrence of each game event in the new game form. This finding suggests an increased involvement. Child-friendly small-sided games (SSG; like the new game form) will help to promote children in the best way and inspire them to play soccer for a long time.

Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify tissue-specific and general gene-regulatory landscapes in the wide breadth of CD8+ TIL functional states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor entity-matching samples, and prioritize key elements by super-enhancer analysis. Our results reveal a human core chromatin trajectory to TIL dysfunction and identify involved key enhancers, transcriptional regulators, and deregulated target genes in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor infiltrating lymphocytes.

Background Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors for which response to immunotherapies is not well established. Therefore, it is important to risk-stratify and identify STS patients who will most likely benefit from these treatments. Results To reveal shared and distinct methylation signatures present in STS, we performed unsupervised deconvolution of DNA methylation data from the TCGA sarcoma and an independent validation cohort. We showed that leiomyosarcoma can be subclassified into three distinct methylation groups. More importantly, we identified a component associated with tumor-infiltrating leukocytes, which suggests varying degrees of immune cell infiltration in STS subtypes and an association with prognosis. We further investigated the genomic alterations that may influence tumor infiltration by leukocytes including RB1 loss in undifferentiated pleomorphic sarcomas and ELK3 amplification in dedifferentiated liposarcomas. Conclusions In summary, we have leveraged unsupervised methylation-based deconvolution to characterize the immune compartment and molecularly stratify subtypes in STS, which may benefit precision medicine in the future.

Murine regulatory T (Treg) cells in tissues promote tissue homeostasis and regeneration. We sought to identify features that characterize human Treg cells with these functions in healthy tissues. Single-cell chromatin accessibility profiles of murine and human tissue Treg cells defined a conserved, microbiota-independent tissue-repair Treg signature with a prevailing footprint of the transcription factor BATF. This signature, combined with gene expression profiling and TCR fate mapping, identified a population of tissue-like Treg cells in human peripheral blood that expressed BATF, chemokine receptor CCR8 and HLA-DR. Human BATF+CCR8+ Treg cells from normal skin and adipose tissue shared features with nonlymphoid T follicular helper-like (Tfh-like) cells, and induction of a Tfh-like differentiation program in naive human Treg cells partially recapitulated tissue Treg regenerative characteristics, including wound healing potential. Human BATF+CCR8+ Treg cells from healthy tissue share features with tumor-resident Treg cells, highlighting the importance of understanding the context-specific functions of these cells.

Summary Specialized regulatory T (Treg) cells accumulate and perform homeostatic and regenerative functions in nonlymphoid tissues. Whether common precursors for nonlymphoid-tissue Treg cells exist and how they differentiate remain elusive. Using transcription factor nuclear factor, interleukin 3 regulated (Nfil3) reporter mice and single-cell RNA-sequencing (scRNA-seq), we identified two precursor stages of interleukin 33 (IL-33) receptor ST2-expressing nonlymphoid tissue Treg cells, which resided in the spleen and lymph nodes. Global chromatin profiling of nonlymphoid tissue Treg cells and the two precursor stages revealed a stepwise acquisition of chromatin accessibility and reprogramming toward the nonlymphoid-tissue Treg cell phenotype. Mechanistically, we identified and validated the transcription factor Batf as the driver of the molecular tissue program in the precursors. Understanding this tissue development program will help to harness regenerative properties of tissue Treg cells for therapy., Graphical Abstract, Highlights • Two precursor stages of ST2+ nonlymphoid-tissue Tregs are evident in the spleen and LNs • Precursor stages are defined by differential expression of Nfil3, PD1, and Klrg1 • Chromatin accessibility and scRNA-seq suggests a stepwise precursor reprogramming • Batf drives the molecular tissue program in the precursors, Whether a common precursor exists for nonlymphoid-tissue Treg cells is unclear. Delacher et al. identify two precursor stages for tissue-resident ST2+ Treg cells. These precursors undergo a stepwise reprogramming in the lymphoid organs toward the nonlymphoid-tissue Treg cell phenotype. Chromatin accessibility profiling identified Batf as a key driver of the tissue program in the progenitor cells.

The amount of data available in banking, finance and economics steadily increases due to the ongoing technological progress and the continuing digitalization. A key element of many econometric models for analyzing this data are methods for assessing dependencies, cross-sectionally as well as intertemporally. For this reason, the thesis is centered around statistical and econometric methods for dependence modeling with applications in financial econometrics. The first part of this cumulative dissertation consists of three contributions. The first contribution provides a thorough explanation of the partial copula. It is a natural generalization of the partial correlation coefficient and several of its properties are investigated. In the second contribution, a different multivariate generalization of the partial correlation, the partial vine copula (PVC), is introduced. The PVC is a specific simplified vine copula (SVC) consisting of bivariate higher-order partial copulas, which are copula-based generalizations of sequentially computed partial correlations. Several properties of the PVC are presented and it is shown that, if SVCs are considered as approximations of multivariate distributions, the PVC has a special role as it is the limit of stepwise estimators. The third contribution introduces statistical tests for the simplifying assumption with a special focus on high-dimensional vine copulas. We propose a computationally feasible test for the simplifying assumption in high-dimensions, which is successfully applied to data sets with up to 49 dimensions. The novel test procedure is based on a decision tree which is used to identify the possibly strongest violation of the simplifying assumption. The asymptotic distribution of the test statistic is derived under consideration of estimation uncertainty in the copula parameters. The finite sample performance is analyzed in an extensive simulation study and the results show that the power of the test only slightly decreases in the dimensionality of the test problem. In the second part of the dissertation, the assessment of risk measures is studied with a special focus on the financial return data used for estimation. It is shown that the choice of the sampling scheme can greatly affect the results of risk assessment procedures if the assessment frequency and forecasting horizon are fixed. Specifically, we study sequences of variance estimates and show that they exhibit spurious seasonality, if the assessment frequency is higher than the sampling frequency of non-overlapping return data. The root cause of spurious seasonality is identified by deriving the theoretical autocorrelation function of sequences of variance estimates under general assumptions. To overcome spurious seasonality, alternative variance estimators based on overlapping return data are suggested. The third part of the dissertation is about state space methods for systems with lagged states in the measurement equation. Recently, a low-dimensional modified Kalman filter and smoother for such systems was proposed in the literature. Special attention is paid to the modified Kalman smoother, for which it is shown that the suggested smoother in general does not minimize the mean squared error (MSE). The correct MSE-minimizing modified Kalman smoother is derived and computationally more efficient smoothing algorithms are discussed. Finally, a comparison of the competing smoothers with regards to the MSE is performed.