Synthesen und absolute Konfigurationen von Piperidinolalkaloiden : Arbeiten zur Darstellung von Epothilon ; chirale [beta]-Hydroxycarbonsäureester als Intermediate in der Naturstoffsynthese

[no abstract

The chemistry of sulfur and nitrogen species in a fog system A multiphase approach

Concentration and phase distribution of sulfur and nitrogen species during a particular fog episode in the Po Valley are experimentally described in this paper. Chemical measurements were carried out simultaneously at different heights within the fog layer, up to 50 m. Microphysical and meteorological parameters necessary for the description of the fog multiphase system were also concurrently measured as a function of height. The fog cycle (formation, evolution, dissipation) is described in terms of the total acidity of a unit volume of air containing gas species, interstitial aerosol particles and fog droplets. The fog system was not closed and input of acidic and basic components was observed during fog evolution. The driving force which determines the acidity of the fog multiphase atmospheric system was found to be the presence of NH 3 and its partitioning among the different phases. A strong decrease of fog water pH (from 5.6 down to 2.8) was observed during fog evolution and was attributed to a HNO 3 input to the system. These acidic and basic inputs are described in terms of a titration/back-titration process of the fog system. The SO 2 oxidation process in fog water was found to be of minor importance in determining the SO 4 = concentration within the fog system, due to both low SO 2 concentration and limited oxidant availability during the experiment. DOI: 10.1034/j.1600-0889.1992.t01-4-00005.

Physical activity monitoring in Alzheimer’s disease during sport interventions: a multi-methodological perspective

IntroductionAssessment methods for physical activity and fitness are of upmost importance due to the possible beneficial effect of physical conditioning on neurodegenerative diseases. The implementation of these methods can be challenging when examining elderly or cognitively impaired participants. In the presented study, we compared three different assessment methods for physical activity from the Dementia-MOVE trial, a 6-months intervention study on physical activity in Alzheimer’s disease. The aim was to determine the comparability of physical activity assessments in elderly participants with cognitive impairment due to Alzheimer’s disease.Material or methods38 participants (mean age 70 ± 7 years) with early-stage Alzheimer’s disease (mean MoCA 18.84 ± 4.87) were assessed with (1) fitness trackers for an average of 12 (± 6) days, (2) a written diary on daily activities and (3) a questionnaire on physical activity at three intervention timepoints. For comparison purposes, we present a transformation and harmonization method of the physical assessment output parameters: Metabolic equivalent of task (MET) scores, activity intensity minutes, calorie expenditure and moderate-to-vigorous physical activity (MVPA) scores were derived from all three modalities. The resulting parameters were compared for absolute differences, correlation, and their influence by possible mediating factors such as cognitive state and markers from cerebrospinal fluid.ResultsParticipants showed high acceptance and compliance to all three assessment methods. MET scores and MVPA from fitness trackers and diaries showed high overlap, whilst results from the questionnaire suggest that participants tended to overestimate their physical activity in the long-term retrospective assessment. All activity parameters were independent of the tested Alzheimer’s disease parameters, showing that not only fitness trackers, but also diaries can be successfully applied for physical activity assessment in a sample affected by early-stage Alzheimer’s disease.DiscussionOur results show that fitness trackers and physical activity diaries have the highest robustness, leading to a highly comparable estimation of physical activity in people with Alzheimer’s disease. As assessed parameters, it is recommendable to focus on MET, MVPA and on accelerometric sensor data such as step count, and less on activity calories and different activity intensities which are dependent on different variables and point to a lower reliability

mpimp-comas/2024_pahl_ziegler_darkchemmatter: Initial release

<p>Changed author list. Added Sandra Koska.</p&gt

mpimp-comas/2024_pahl_ziegler_darkchemmatter: Initial release

<p>Initial release for publication.</p&gt

mpimp-comas/2022_pahl_ziegler_subprofiles: Release for cluster MitoStress

<p>Added new cluster MitoStress.</p&gt

Spacial Score – A Comprehensive Topological Indicator for Small Molecule Complexity

The fraction of sp3 hybridised carbons (Fsp3) and the fraction of stereogenic carbons (FCstereo) are two widely employed scores of molecular complexity with a strong link to biologically relevant features such as frequency, potency and selectivity of protein binding. However, due to their simplistic nature, they do not comprehensively express molecular topology and they often do not match the chemical intuition of complexity. We propose the spacial score (SPS) as an empirical scoring system that builds upon the principle underlying Fsp3 and FCstereo and expresses the spacial complexity of a compound in a uniform manner and on a highly granular scale for convenient ranking of and comparison between molecules. The size-normalised SPS (nSPS) can differentiate distributions of natural products and synthetic compounds and is applicable in the analysis of biological activity data. Analysis of the ChEMBL database revealed general trends of increasing selectivity and potency with increasing nSPS. Notably, SPS can also be used advantageously in planning and analysis of synthesis programs for direct comparison of chemical transformations and intermediates in reaction sequences, for instance in natural product total syntheses

Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening

Abstract Plastic components are essential in the pharmaceutical industry, encompassing container closure systems, laboratory handling equipment, and single-use systems. As part of their material qualification process, studies on interactions between plastic contact materials and process solutions or drug products are conducted. The assessment of single-use systems includes their potential impact on patient safety, product quality, and process performance. This is particularly crucial in cell and gene therapy applications since interactions with the plastic contact material may result in an adverse effect on the isolated therapeutic human cells. We utilized the cell painting assay (CPA), a non-targeted method, for profiling the morphological characteristics of U2OS human osteosarcoma cells in contact with chemicals related to plastic contact materials. Specifically, we conducted a comprehensive analysis of 45 common plastic extractables, and two extracts from single-use systems. Results of the CPA are compared with a standard cytotoxicity assay, an osteogenesis differentiation assay, and in silico toxicity predictions. The findings of this feasibility study demonstrate that the device extracts and most of the tested compounds do not evoke any measurable biological changes on the cells (induction  ≤ 5%) among the 579 cell features measured at concentrations  ≤ 50 µM. CPA can serve as an important assay to reveal unique information not accessible through quantitative structure–activity relationship analysis and vice versa. The results highlight the need for a combination of in vitro and in silico methods in a comprehensive assessment of single-use equipment utilized in advanced therapy medicinal products manufacturing

Pseudo-Natural Products Occur Frequently in Biologically Relevant Compounds

A new methodology for classifying fragment combinations and characterizing pseudo-natural products (PNPs) is described. The source code is based on open-source tools and is organized as a Python package. Tasks can be executed individually or within the context of scalable, robust workflows. First, structures are standardized and duplicate entries are filtered out. Then, molecules are probed for the presence of predefined fragments. For molecules with more than one match, fragment combinations are classified. The algorithm considers the pair-wise relative position of fragments within the molecule (fused atoms, linkers, intermediary rings), resulting in 18 different possible fragment combination categories. Finally, all combinations for a given molecule are assembled into a fragment combination graph, with fragments as nodes and combination types as edges. This workflow was applied to characterize PNPs in the ChEMBL database via comparison of fragment combination graphs with Natural Product (NP) references, represented by the Dictionary of Natural Products. The Murcko fragments extracted from 2,000 structures previously described were used to define NP-fragments. The results indicate that ca. 23% of the biologically relevant compounds listed in ChEMBL comply to the PNP definition, and that, therefore, PNPs occur frequently among known biologically relevant small molecules. The majority (>95%) of PNPs contains two to four fragments, mainly (>95%) distributed in five different combination types. These findings may provide guidance for the design of new PNPs

Identification of Readily Available Pseudo-Natural Products

Pseudo-natural products (PNPs) combine fragments derived from NPs in ways that are not found in nature, and may lead to the discovery of novel chemotypes for unexpected targets or the identification of unprecedented bioactivities. PNPs have increasingly been explored in recent drug discovery programs, and are strongly enriched in clinical compounds. We describe how a large number of structurally different PNPs can be accessed readily and without the need to execute labor- and time intensive synthesis programs. We employed an improved version of the previously reported natural product fragment combination (NPFC) tool to analyze the full library of 3.5M synthetic small molecules and screening libraries from Enamine for PNP content, assessed the spatial complexity of Enamine-PNPs using the recently developed normalized Spatial Score (nSPS) and evaluated the bioactivity of a selected subset of Enamine-PNPs in the unbiased morphological cell painting assay. A major fraction (32%; 1.1 million compounds) of the Enamine library are PNPs which contain a significant number of compounds with unexpected and probably new bioactivity