Studien zur Synthese neuer Derivate gegen Sarkopenie und Kachexie

Muskeldegeneration im Alter oder als Komplikation anderer Erkrankungen (Sarkopenie und Kachexie) sind schwerwiegende Syndrome, die die Lebensqualität und die Prognose für Krankheiten deutlich reduzieren. Verschiedenste Therapieansätze zur Behandlung dieses Syndroms wurden bisher ohne durchschlagenden Erfolg entwickelt. Ein mögliches therapeutisches Target ist das Signalpeptid Myostatin (MSTN), welches eine Schlüsselrolle in der Regulation des Muskelwachstums ausübt. In diesem Projekt wurden aufbauend auf zwei Referenzverbindungen, einem Benzimidazol-Derivat (Referenz 7) und einem 1H-[3,4-d]-Pyrazolopyrimidin-Derivat (Referenz 8), neue „Small Molecules“ mittels computergestütztem Docking designed und synthetisiert. Dazu wurden modulare Syntheserouten zu den beiden Referenzverbindungen entworfen, wobei mitunter literaturbekannte Methoden auf neue Substrate erweitert wurden. Über diese Sequenzen konnten insgesamt 69 Verbindungen (Referenz 7 + 31 Derivate und Referenz 8 + 36 Derivate) erfolgreich hergestellt werden. Die Ergebnisse der biologischen Charakterisierung der Verbindungen in einem zellbasierten Reportergen-Assay floss in das Design der jeweils nächsten Generation von Derivaten ein. So konnten mehrere hochpotente Verbindungen (IC50-Werte <10 nM) entwickelt werden, wobei die meisten Derivate von 8 abgeleitet wurden und nur ein potentes Derivat von 7 synthetisiert wurde. In Folgeprojekten sollen die aktivsten Verbindungen weitergehend charakterisiert und der genau Wirkmechanismus entschlüsselt werden

A Combination of Ion Implantation and High-Temperature Annealing: The Origin of the 265 nm Absorption in AlN

The commonly observed absorption around 265 nm in AlN is hampering the outcoupling efficiency of light-emitting diodes (LEDs) emitting in the UV-C regime. Carbon impurities in the nitrogen sublattice (CN) of AlN are believed to be the origin of this absorption. A specially tailored experiment using a combination of ion implantation of boron, carbon, and neon with subsequent high-temperature annealing allows to separate the influence of intrinsic point defects and carbon impurities regarding this absorption. Herein, the presented results reveal the relevance of the intrinsic nitrogen-vacancy defect VN. This is in contradiction to the established explanation based on CN defects as the defect causing the 265 nm absorption and will be crucial for further UV-LED improvement. Finally, in this article, a new interpretation of the 265 nm absorption is introduced, which is corroborated by density functional theory (DFT) results from the past decade, which are reviewed and discussed based on the new findings

MRI Extracellular Volume Fraction in Liver Fibrosis-A Comparison of Different Time Points and Blood Pool Measurements.

BACKGROUND Extracellular volume (ECV) correlates with the degree of liver fibrosis. PURPOSE To analyze the performance of liver MRI-based ECV evaluations with different blood pool measurements at different time points. STUDY TYPE Prospective. SAMPLE 73 consecutive patients (n = 31 females, mean age 56 years) with histopathology-proven liver fibrosis. FIELD STRENGTH/SEQUENCE 3T acquisition within 90 days of biopsy, including shortened modified look-locker inversion recovery T1 mapping. ASSESSMENT Polygonal regions of interest were manually drawn in the liver, aorta, vena cava, and in the main, left and right portal vein on four slices before and after Gd-DOTA administration at 5/10/15 minutes. ECV was calculated 1) on one single slice on portal bifurcation level, and 2) averaged over all four slices. STATISTICAL TESTS Parameters were compared between patients with fibrosis grades F0-2 and F3-F4 with the Mann-Whitney U and fishers exact test. ROC analysis was used to assess the performance of the parameters to predict F3-4 fibrosis. A P-value <0.05 was considered statistically significant. RESULTS ECV was significantly higher in F3-4 fibrosis (35.4% [33.1%-37.6%], 36.1% [34.2%-37.5%], and 37.0% [34.8%-39.2%] at 5/10/15 minutes) than in patients with F0-2 fibrosis (33.3% [30.8%-34.8%], 33.7% [31.6%-34.7%] and 34.9% [32.2%-36.0%]; AUC = 0.72-0.75). Blood pool T1 relaxation times in the aorta and vena cava were longer on the upper vs. lower slices at 5 minutes, but not at 10/15 minutes. AUC values were similar when measured on a single slice (AUC = 0.69-0.72) or based on blood pool measurements in the cava or portal vein (AUC = 0.63-0.67 and AUC = 0.65-0.70). DATA CONCLUSION Liver ECV is significantly higher in F3-4 fibrosis compared to F0-2 fibrosis with blood pool measurements performed in the aorta, inferior vena cava, and portal vein at 5, 10, and 15 minutes. However, a smaller variability was observed for blood pool measurements between slices at 15 minutes. LEVEL OF EVIDENCE 1 TECHNICAL EFFICACY: Stage 3

Energy consumption-based accounts : A comparison of results using different energy extension vectors

Increasing attention has been focussed on the use of consumption-based approaches to energy accounting via input-output (IO) methods. Of particular interest is the examination of energy supply chains, given the associated risks from supply-chain issues, including availability shocks, taxes on fossil fuels and fluctuating energy prices. Using a multiregional IO (MRIO) database to calculate energy consumption-based accounts (CBA) allows analysts to both determine the quantity and source of energy embodied in products along the supply chain. However, it is recognised in the literature that there is uncertainty as to the most appropriate type of energy data that should be employed in an IO framework. Questions arise as to whether an energy extension vector should show where the energy was extracted or where it was used (burnt). In order to address this gap, we undertake the first empirical MRIO analysis of an energy CBA using both vectors. Our results show that both the energy-extracted and energy-used vectors produce similar estimates of the overall energy CBA for the UK—notably 45% higher than territorial energy requirements. However, at a more granular level, the results show that the type of vector that should be employed ultimately depends on the research question that is considered. For example, the energy-extracted vector reveals that just 20% of the UK's energy CBA includes energy extracted within the UK, an issue that is upmost importance for energy security policy. At the other end, the energy-used vector allows for the attribution of actual energy use to industry sectors, thereby enabling a better understanding of sectoral efficiency gains. These findings are crucial for users and developers of MRIO databases who undertake energy CBA calculations. Since both vectors appear useful for different energy questions, the construction of robust and consistent energy-used and energy-extracted extension vectors as part of commonly-used MRIO model databases is encouraged

Artificial Intelligence and Interstitial Lung Disease: Diagnosis and Prognosis.

Interstitial lung disease (ILD) is now diagnosed by an ILD-board consisting of radiologists, pulmonologists, and pathologists. They discuss the combination of computed tomography (CT) images, pulmonary function tests, demographic information, and histology and then agree on one of the 200 ILD diagnoses. Recent approaches employ computer-aided diagnostic tools to improve detection of disease, monitoring, and accurate prognostication. Methods based on artificial intelligence (AI) may be used in computational medicine, especially in image-based specialties such as radiology. This review summarises and highlights the strengths and weaknesses of the latest and most significant published methods that could lead to a holistic system for ILD diagnosis. We explore current AI methods and the data use to predict the prognosis and progression of ILDs. It is then essential to highlight the data that holds the most information related to risk factors for progression, e.g., CT scans and pulmonary function tests. This review aims to identify potential gaps, highlight areas that require further research, and identify the methods that could be combined to yield more promising results in future studies

Ask Smart to Get Smart: Mathematische Ausgaben generativer KI-Sprachmodelle verbessern durch gezieltes Prompt Engineering

Der Beitrag beschäftigt sich mit den derzeitigen mathematischen Fähigkeiten des generativen KI-Spachmodells ChatGPT in Bezug auf das Lösen mathematischer Probleme. Um für den schulischen Nutzen des Modells die Zuverlässigkeit und Nachvollziehbarkeit von mathematischen Ausgaben zu optimieren, stellen wir im Beitrag unterschiedliche Prompt-Techniken vor und untersuchen ihren Effekt in Modellvalidierungen anhand einer arithmetischen und einer algebraischen Problemlöseaufgabe

Distinct Clinical and Laboratory Patterns of Pneumocystis jirovecii Pneumonia in Renal Transplant Recipients.

Late post-transplant Pneumocystis jirovecii pneumonia (PcP) has been reported in many renal transplant recipients (RTRs) centers using universal prophylaxis. Specific features of PcP compared to other respiratory infections in the same population are not well reported. We analyzed clinical, laboratory, administrative and radiological data of all confirmed PcP cases between January 2009 and December 2014. To identify factors specifically associated with PcP, we compared clinical and laboratory data of RTRs with non-PcP. Over the study period, 36 cases of PcP were identified. Respiratory distress was more frequent in PcP compared to non-PcP (tachypnea: 59%, 20/34 vs. 25%, 13/53, p = 0.0014; dyspnea: 70%, 23/33 vs. 44%, 24/55, p = 0.0181). In contrast, fever was less frequent in PcP compared to non-PcP pneumonia (35%, 11/31 vs. 76%, 42/55, p = 0.0002). In both cohorts, total lymphocyte count and serum sodium decreased, whereas lactate dehydrogenase (LDH) increased at diagnosis. Serum calcium increased in PcP and decreased in non-PcP. In most PcP cases (58%, 21/36), no formal indication for restart of PcP prophylaxis could be identified. Potential transmission encounters, suggestive of interhuman transmission, were found in 14/36, 39% of patients. Interhuman transmission seems to contribute importantly to PcP among RTRs. Hypercalcemia, but not elevated LDH, was associated with PcP when compared to non-PcP