Curse and Blessing of Non-proteinogenic Parts in Computational Enzyme Engineering

Enzyme engineering aims to improve or install a new function in biocatalysts for applications ranging from chemical synthesis to biomedicine. For decades, computational techniques have been developed to predict the effect of protein changes and design new enzymes. However, these techniques may have been optimized to deal with proteins composed of the standard amino acid alphabet, while the function of many enzymes relies on non-proteogenic parts like cofactors, nucleic acids, and post-translational modifications. Enzyme systems containing such molecules might be handled or modeled improperly by computational tools, and thus be unsuitable, or require additional tweaking, parameterization, or preparation. In this review, we give an overview of common and recent tools and workflows available to computational enzyme engineers. We highlight the various pitfalls that come with including non-proteogenic compounds in computations and outline potential ways to address common issues. Finally, we showcase successful examples from literature that computationally engineered such enzymes.</p

Embolization Therapy for Pancreas-Related Bleeding: A Retrospective Analysis With Focus on End-Organ Ischemia

Die transarterielle Embolisation (TAE) hat die offene chirurgische Therapie bei der Behandlung akuter arterieller Blutungen und der Versorgung von (Pseudo-) Aneurysmen in den letzten Jahren zunehmend abgelöst. Insbesondere die Coilembolisation von Arterien erweist sich als komplikationsarmes und effektives Verfahren mit niedriger Mortalitätsrate und zeigt sich darin der chirurgischen Therapie überlegen. Ziel der vorliegenden Studie war es, den technischen und klinischen Erfolg bezüglich der transarteriellen Embolisation (TAE) pankreasnaher Gefäße zu analysieren. Zusätzlich sollten die Auswirkungen der Coilembolisation im arteriellen peripankreatischen Stromgebiet auf die Perfusion von Pankreas und Milz untersucht werden. Dazu wurden über einen Zeitraum von zehn Jahren die Daten aller Patienten retrospektiv untersucht, die sich einer Embolisation einer pankreasnahen Arterie am Universitätsklinikum der Technischen Universität München unterziehen mussten. Alle Patienten konnten initial erfolgreich embolisiert werden, sodass Blutungen und (Pseudo-)Aneurysmen suffizient ausgeschaltet wurden. Dabei zeigten sich besonders viele Arrosionsblutungen, sowie Pseudoaneurysmen. Diese entstanden mehrheitlich im Rahmen einer Pankreatitis oder entwickelten sich postoperativ nach Pankreasresektionen. Bezüglich einer Schädigung des Pankreas durch Minderperfusion nach Embolisation zuführender Arterien, konnte keine relevante Schädigung des Parenchyms festgestellt werden. Bezüglich einer möglichen Schädigung der Milz zeigte sich eine erhöhte Wahrscheinlichkeit für eine Splenektomie je näher die A. lienalis am Milzhilus coilembolisiert wurde. Daher ist es wahrscheinlich, dass die Kollateralisierung durch das hilusnahe Coiling verhindert wird und es konsekutiv zur Infarzierung mit möglicher Abszedierung des Milzparenchyms kommt.Transarterial Embolisation (TAE) has only recently replaced surgery in the treatment of acute arterial bleeding and therapy of (pseudo-) aneurysms. Especially embolisation with coils claims superiority over surgery by being a safe and effective option with low mortality rates. The aim of this study was to analyse the technical and clinical success of TAE. Additionally we focused on its effects on the perfusion of spleen and pancreas. We analysed the data of all patients undergoing TAE of peripancreatic arteries over a 10 year time period at the University Hospital of Technical University of Munich. All patients were treated successfully with a majority of pseudoaneurysms and errosive bleedings being embolised. Those developed mainly due to pancretitis or after pancreatic surgery. There was no major damage of pancreatic parenchyma after TAE. However regarding damage oft the spleen we found out that there was an increased risk for spleenectomy when coils were placed closer to the hilus of the spleen. It is therefore likely that collateralisation of the arterial blood flow towards the spleen is being disrupted and patients are at a higher risk to develop spleen infarction as a consequence

A deep learning based classification of atmospheric circulation types over Europe: projection of future changes in a CMIP6 large ensemble

High- and low pressure systems of the large-scale atmospheric circulation in the mid-latitudes drive European weather and climate. Potential future changes in the occurrence of circulation types are highly relevant for society. Classifying the highly dynamic atmospheric circulation into discrete classes of circulation types helps to categorize the linkages between atmospheric forcing and surface conditions (e.g. extreme events). Previous studies have revealed a high internal variability of projected changes of circulation types. Dealing with this high internal variability requires the employment of a single-model initial-condition large ensemble (SMILE) and an automated classification method, which can be applied to large climate data sets. One of the most established classifications in Europe are the 29 subjective circulation types called Grosswetterlagen by Hess & Brezowsky (HB circulation types). We developed, in the first analysis of its kind, an automated version of this subjective classification using deep learning. Our classifier reaches an overall accuracy of 41.1% on the test sets of nested cross-validation. It outperforms the state-of-the-art automatization of the HB circulation types in 20 of the 29 classes. We apply the deep learning classifier to the SMHI-LENS, a SMILE of the Coupled Model Intercomparison Project phase 6, composed of 50 members of the EC-Earth3 model under the SSP37.0 scenario. For the analysis of future frequency changes of the 29 circulation types, we use the signal-to-noise ratio to discriminate the climate change signal from the noise of internal variability. Using a 5%-significance level, we find significant frequency changes in 69% of the circulation types when comparing the future (2071–2100) to a reference period (1991–2020)