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"Ludwig, Thomas"
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Ernst Ludwig Kirchner : imaginary travels
Throughout Ernst Ludwig Kirchner's career, one unifying theme emerges - the search for what he saw as unadulterated and primal. This volume explores the far-reaching influence of non-western art on Kirchner's oeuvre and the importance of his life in Davos, Switzerland, where he found a temporary peace despite the impending threat of censorship by the Nazis. Throughout the chapters of this book are reproductions of Kirchner's paintings as well as his sculptures, woodcuts, sketches, drawings, textiles, carvings, and furniture. Archival material in the form of letters and diary entries offer an unprecedented look into the artist's creative process. This study of one of the most talented and influential German Expressionist painters draws compelling conclusions about the influence of the imaginary on his work.
Book
A global linearized framework for modelling shear dispersion and turbulent diffusion of passive scalar fluctuations
In the field of gas-turbine engineering, entropy waves and fluctuations in fuel–air mixing are of significant importance. The impact of either mechanism on thermoacoustic stability of the engine and combustion noise considerably depends on how they are convected in the combustion chamber. In this work, a novel method is employed to analyse their convection. Both effects are modelled using a transport equation of a passive scalar linearized around the mean field. The linearized transport equation is discretized using finite elements. It is shown that turbulent passive scalar transport can be described by an eddy diffusivity in the linear framework. The method is furthermore validated against direct numerical simulation (DNS) of passive scalar transport in a turbulent channel flow. Taking the mean flow from the DNS as input, the method reproduces transport of periodic passive scalar fluctuations with high accuracy at negligible numerical expense. Previous studies investigated destructive interference of the passive scalar due to a non-uniform mean flow profile, a process termed mean flow shear dispersion. The method introduced in this study, however, allows us to additionally quantify the impact of molecular and turbulent diffusion. For the channel flow under investigation, mean flow shear dispersion is the dominant mechanism at low frequencies while, at higher frequencies, turbulent diffusion needs to be accounted for to reproduce the DNS results. Molecular diffusion, however, only has a minor effect on the overall convection in the turbulent channel flow.
Journal Article
Generation of pluripotent stem cells from patients with type 1 diabetes
Type 1 diabetes (T1D) is the result of an autoimmune destruction of pancreatic β cells. The cellular and molecular defects that cause the disease remain unknown. Pluripotent cells generated from patients with T1D would be useful for disease modeling. We show here that induced pluripotent stem (iPS) cells can be generated from patients with T1D by reprogramming their adult fibroblasts with three transcription factors (OCT4, SOX2, KLF4). T1D-specific iPS cells, termed DiPS cells, have the hallmarks of pluripotency and can be differentiated into insulin-producing cells. These results are a step toward using DiPS cells in T1D disease modeling, as well as for cell replacement therapy.
Journal Article
Enhancing the annotation of small ORF-altering variants using MORFEE: introducing MORFEEdb, a comprehensive catalog of SNVs affecting upstream ORFs in human 5′UTRs
Non-canonical small open reading frames (sORFs) are among the main regulators of gene expression. The most studied of these are upstream ORFs (upORFs) located in the 5′-untranslated region (UTR) of coding genes. Internal ORFs (intORFs) in the coding sequence and downstream ORFs (dORFs) in the 3′UTR have received less attention. Different bioinformatics tools permit the prediction of single nucleotide variants (SNVs) altering upORFs, mainly those creating AUGs or deleting stop codons, but no tool predicts variants altering non-canonical translation initiation sites and those altering intORFs or dORFs. We propose an upgrade of our MORFEE bioinformatics tool to identify SNVs that may alter all types of sORFs in coding transcripts from a VCF file. Moreover, we generate an exhaustive catalog, named MORFEEdb, reporting all possible SNVs altering existing upORFs or creating new ones in human transcripts, and provide an R script for visualizing the results. MORFEEdb has been implemented in the public platform Mobidetails. Finally, the annotation of ClinVar variants with MORFEE reveals that > 45% of UTR-SNVs can alter upORFs or dORFs. In conclusion, MORFEE and MORFEEdb have the potential to improve the molecular diagnosis of rare human diseases and to facilitate the identification of functional variants from genome-wide association studies of complex traits.
Journal Article
Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination
B cells producing high-affinity antibodies are destined to differentiate into memory B cells and plasma cells, but the mechanisms leading to those differentiation pathways are mostly unknown. Here we report that the transcription factor IRF4 is required for the generation of plasma cells. Transgenic mice with conditional deletion of
Irf4
in germinal center B cells lacked post–germinal center plasma cells and were unable to differentiate memory B cells into plasma cells. Plasma cell differentiation required IRF4 as well as the transcriptional repressor Blimp-1, which both acted 'upstream' of the transcription factor XBP-1. In addition, IRF4-deficient B cells had impaired expression of activation-induced deaminase and lacked class-switch recombination, suggesting an independent function for IRF4 in this process. These results identify IRF4 as a crucial transcriptional 'switch' in the generation of functionally competent plasma cells.
Journal Article
Linear analysis of a swirling jet with a realistic swirler model
The dynamics of an axisymmetrical swirling jet is studied via global linear stability and resolvent analyses. The modeled flow represents a combustor-like swirling jet, that is turbulent, compressible, non-parallel, and enclosed. In particular, the computational domain embeds a realistic axisymmetrical swirler model to resolve the mode conversion process. Swirl fluctuations are non-negligible on this configuration representative of a swirl burner, and match the analytical mode shapes of inertial waves of an inviscid uniform flow as obtained from global stability analysis. The stability map presents two eigenvalues driving a modal amplification. These eigenmodes couple a standing acoustic wave sustained in the mixing duct and the combustion chamber with the Kelvin-Helmholtz mechanism at the mixing duct exit and the acoustic-vorticity mode conversion process at the swirler, and act as a frequency selection criterion. Finally, the most amplified forcing from the resolvent analysis is similar to an unsteady heat source in the combustion chamber, and the identified optimal amplification mechanism is likely to be triggered in reacting flow with unsteady heat release rate.
Journal Article
Murine models for familial pancreatic cancer: Histopathology, latency and drug sensitivity among cancers of Palb2, Brca1 and Brca2 mutant mouse strains
Alterations of the PALB2 tumor suppressor gene have been identified in familial breast, ovarian and pancreatic cancer cases. PALB2 cooperates with BRCA1/2 proteins through physical interaction in initiation of homologous recombination, in maintenance of genome integrity following DNA double-strand breaks. To determine if the role of PALB2 as a linker between BRCA1 and BRCA2 is critical for BRCA1/2-mediated tumor suppression, we generated Palb2 mouse pancreatic cancer models and compared tumor latencies, phenotypes and drug responses with previously generated Brca1/2 pancreatic cancer models. For development of Palb2 pancreatic cancer, we crossed conditional Palb2 null mouse with mice carrying the KrasG12D; p53R270H; Pdx1-Cre (KPC) constructs, and these animals were observed for pancreatic tumor development. Individual deletion of Palb2, Brca1 or Brca2 genes in pancreas per se using Pdx1-Cre was insufficient to cause tumors, but it reduced pancreata size. Concurrent expression of mutant KrasG12D and p53R270H, with tumor suppressor inactivated strains in Palb2-KPC, Brca1-KPC or Brca2-KPC, accelerated pancreatic ductal adenocarcinoma (PDAC) development. Moreover, most Brca1-KPC and some Palb2-KPC animals developed mucinous cystic neoplasms with PDAC, while Brca2-KPC and KPC animals did not. 26% of Palb2-KPC mice developed MCNs in pancreata, which resemble closely the Brca1 deficient tumors. However, the remaining 74% of Palb2-KPC animals developed PDACs without any cysts like Brca2 deficient tumors. In addition, the number of ADM lesions and immune cells infiltrations (CD3+ and F/480+) were significantly increased in Brca1-KPC tumors, but not in Brca2-KPC tumors. Interestingly, the level of ADM lesions and infiltration of CD3+ or F/480+ cells in Palb2-KPC tumors were intermediate between Brca1-KPC and Brca2-KPC tumors. As expected, disruption of Palb2 and Brca1/2 sensitized tumor cells to DNA damaging agents in vitro and in vivo. Altogether, Palb2-KPC PDAC exhibited features observed in both Brca1-KPC and Brca2-KPC tumors, which could be due to its role, as a linker between Brca1 and Brca2.
Journal Article
Field-space autoencoder for scalable climate emulators
High-Resolution Earth system models are essential for capturing local climate change. However, these models are computationally expensive and produce petabyte-scale outputs, limiting their utility for applications such as probabilistic risk assessment. Here, we present the Field-Space Autoencoder, a scalable climate emulation framework based on a spherical compression model that overcomes these challenges. By combining a multi-scale encoding of the input with field-space processing layers, the model efficiently processes multiple spatial scales simultaneously. This approach preserves physical structures significantly better than convolutional baselines. By producing a structured compressed field, it serves as a good baseline for downstream generative emulation. In addition, the model can perform zero-shot super-resolution that maps low-resolution large ensembles and scarce high-resolution data into a shared representation. By training a generative diffusion model on these compressed fields, we demonstrate that our framework can simultaneously learn internal variability from abundant low-resolution data and fine-scale physics from scarce high-resolution data. Our work bridges the gap between the high volume of low-resolution ensemble statistics and the scarcity of high-resolution physical detail.
Journal Article
Degeneralizing instrument approach minima to non instrument runways: a case study for Payerne airport in Switzerland
Instrument approaches to non- instrument runways were made possible by the new approach classification of ICAO. As a conservative solution, the procedure design guidelines by the national civil aviation authorities apply circling minima to those approaches to non-instrument runways. However, the classification as non-instrument runway is very binary. Often a small item causes a reduction from instrument to a non-instrument runway and the circling minima become thus very conservative. Here, two cases are shown, Payerne, a non-instrument runway, and Ouessant with an instrument runway, both equipped very differently but both serving Instrument Flight Rules (IFR) traffic. Solutions for Payerne and other similarly highly equipped non-instrument runways are proposed in order to be able to accommodate at least non-precision minima.
Journal Article
Easy-PSAP: An Integrated Workflow to Prioritize Pathogenic Variants in Sequence Data from a Single Individual
Introduction: Next-generation sequencing (NGS) data analysis has become an integral part of clinical genetic diagnosis, raising the question of variant prioritization. The Population Sampling Probability (PSAP) method has been developed to tackle the issue of variant prioritization in the exome of a single patient, by leveraging allele frequencies from population databases and a variant pathogenicity score. Methods: Here, we present Easy-PSAP, a completely new implementation of the PSAP method comprising two user-friendly and highly adaptable pipelines. Easy-PSAP allows the gene-based recalibration of any in silico pathogenicity prediction score compared to scores of variants seen in the general population, including popular scores like CADD or AlphaMissense. Easy-PSAP can evaluate genetic variants at the scale of a whole exome or a whole genome using information from the latest population and annotation databases. Results: Through simulations on synthetic disease exomes, we show that Easy-PSAP is able to rank more than 50% of causal pathogenic variants in the top 10 variants for an autosomal dominant model of transmission and in top 1 for an autosomal recessive model of transmission. Discussion: These findings, along with the accessibility of the pipeline to both researchers and clinicians, make Easy-PSAP a state-of-the-art tool for variant prioritization in NGS data that can continue to evolve as new frameworks and databases become available. Easy-PSAP is implemented in R and bash within an open-source Snakemake framework. It is available on GitHub alongside conda environments containing the required dependencies (https://github.com/msogloblinsky/Easy-PSAP ).
Journal Article