Gutenberg Open Science (Univ. Mainz)
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Parallel synthesis of 5′-amino-5′-deoxy-adenosine derivatives for focused chemical space exploration and their application as methyltransferase inhibitors
No full textParallel syntheses and their throughput capabilities are powerful tools for the rapid generation of molecule libraries, making them highly beneficial for accelerating hit identification in early-stage drug discovery. Utilizing chemical spaces and virtual libraries enhances time and cost efficiency, enabling the faster exploitation of chemically diverse compounds. In this study, a parallel synthesis method for rapidly generating a 5′-amino-5′-deoxy adenosine-based amide and sulfonamide library of 42 compounds is described with high yields and purity, which is economical and ecological due to the reduced requirements for extensive purification. Methyltransferases recently emerged as promising drug targets. The adenosine-derived library was screened using a fluorescence polarization (FP) assay against model enzymes human DNMT2 and METTL3/14, and SARS-CoV-2 nsp14/10, resulting in the identification of three compounds binding with nanomolar affinity to nsp14/10 and three compounds binding METTL3/14 with low micromolar affinity. To demonstrate the accessibility of a broad variety of adenosine derivatives, a focused virtual chemical space of 25 241 5′-amino-5′-deoxy adenosine amides and sulfonamides, which are accessible via the described synthetic procedure, was generated. This chemical space was further investigated for potential biological applications through virtual screening against nsp14/10 which led to the identification of four additional ligands with low micromolar affinities
Structure-guided design of a methyltransferase-like 3 (METTL3) proteolysis targeting chimera (PROTAC) incorporating an indole–nicotinamide chemotype
No full textMethyltransferase-like 3 (METTL3) is the main catalytic subunit of the m6A methyltransferase complex (MTC) and plays an essential role in various disease indications, including acute myeloid leukemia (AML). Here, we describe the structure-guided design and evaluation of METTL3 proteolysis-targeting chimeras (PROTACs), starting from the potent small-molecule inhibitor STM2457. Across four design generations, we highlight key considerations, particularly regarding the exit vector, linker mechanics, and METTL3-binding chemotype composition. Our most effective PROTAC, AF151, forms a stable complex between the E3 ligase von Hippel–Lindau (VHL) and the target-of-interest METTL3, demonstrating efficient METTL3 degradation (DC50 = 430 nM) in the AML cell line MOLM-13. This molecule candidate exhibits more pronounced effects on viability inhibition (IC50 = 0.45 μM) and more significant m6A level reduction in cancer cells than its non-PRTOAC parent compounds. By incorporating the indole-nicotinamide chemotype as the METTL3-binding recruiter, this PROTAC is structurally distinct from recently published METTL3 PROTACs, expanding the design options for future METTL3 degrader development
Disentangling the interrelations of body mass, egg deposition site, climate and microhabitat use in frogs and salamanders
No full textAmphibians exhibit a large diversity in reproductive and developmental strategies, which in turn are linked to their body size, life history and habitat. Here, we explore why terrestrial egg laying frogs are on average smaller than aquatic egg laying ones and whether this pattern also exists in salamanders. We hypothesized that egg deposition site and body mass are not linked directly across species, but that terrestrial egg layers occur in climates and use microhabitats that favor small masses. To test this, we compiled a dataset on egg deposition site (terrestrial or aquatic), development mode (biphasic with larvae or direct development without larvae), body mass, microhabitat use (water-dependent, ground-dwelling or arboreal) and climate within their distribution area (temperature, precipitation and seasonality in both) of 3091 frog and 244 salamander species. We analyzed the interrelations between these traits and environmental factors by using a cross-species approach and phylogenetic generalized least squares analysis. Body masses increased along a gradient from warm, humid and unseasonal climates to cold, dry and seasonal climates in frogs and salamanders. Terrestrial egg deposition was constrained to warm, humid and unseasonal climates only in frogs. Terrestrial eggs and an arboreal microhabitat use were linked in frogs and salamanders, and arboreal frogs were smaller than non-arboreal ones. We confirmed that frogs with terrestrial eggs had smaller average body masses than those with aquatic eggs, irrespective of their development mode, but this difference disappeared when we corrected body masses for the effects of climate and microhabitat use. In salamanders, however, egg deposition site and development mode were neither directly related to body mass, nor indirectly via the effects of climate and microhabitat use. Our results suggest that thermal and hydric environmental conditions determine the geographical distribution of body mass and reproductive strategies in amphibians and set the framework for their evolution
Bulk segregant analysis reveals genomic regions associated with imidacloprid resistance in the Colorado potato beetle
No full textGiven the increased accessibility of genomic techniques, the speed of evolution of resistance, and the large number of genes involved in resistance, investigations into the genetic basis of resistance in more species are pertinent. Despite being an important agricultural pest, only a limited number of genetic mapping studies based on crossed populations have been performed to identify genes involved in resistance in the Colorado potato beetle (CPB, Leptinotarsa decemlineata Say). Here, we performed bulk segregant analysis on a mapping population generated by creating advanced intercross lines from five European strains of CPB. We identified eight peaks across chromosomes 1, 8, 10, and 16 involved in resistance against the neonicotinoid, imidacloprid. We identified 337 genes within these peaks and shortlisted three candidates based on gene expression and functional annotation. Among the three candidates identified, we found that an ABC transporter and a galactosyl transferase are expressed in relatively higher amounts in a relatively more susceptible strain than in a resistant strain. We attempted to validate the role of these two genes in insecticide resistance by knocking them down in a resistant strain using RNA interference (RNAi) and performing toxicity experiments. Contrary to our expectations, we found that the activation of the RNAi machinery itself reduced imidacloprid resistance, and the effect is not specific to the tested candidate genes. This raises concern about the suitability of using RNAi for validating insecticide resistance mechanisms in CPB
Effect of pharmacist-led medication reviews on appropriateness of prescribing in patients with dementia : results from the cluster randomized controlled “DemStepCare” study
No full textBackground
Patients with dementia (PwD) are often geriatric patients treated with multimedication increasing the risk of drug-related problems (DRP) and inappropriate prescriptions. Pharmacist-led medication reviews are effective to solve DRPs and to improve medication appropriateness. The Medication Appropriateness Index (MAI) is a reliable, valid and standardised tool for detecting multiple dimensions of inappropriate prescribing. The research aimed to evaluate the impact of pharmacist-led medication reviews on medication appropriateness of PwDs as part of the DemStepCare study, using the MAI to categorise potentially inappropriate prescriptions.
Methods
Comprehensive medication reviews were performed for PwD treated as outpatients over 39 months in the longitudinal, cluster-randomized controlled DemStepCare study by a clinical pharmacist utilizing the project-specific, electronic patient record. Modified MAI scores were calculated at baseline and over the course of the study in the intervention group (IG) and control group (CG) at predefined time points. Only in the interventional arm, responsible GPs were informed about the result of the medication review and the pharmacist’s recommendation to improve medication appropriateness.
Results
198 PwDs were enrolled in the IG and 47 PwDs in the CG (intention-to-treat collective). For IG patients, the modified MAI sum (SS) and patient score (PS) decreased significantly (p < 0.001) until t1, i.e. over the first 9 or 11 months of the study (baseline: SS = 15.24 ± 12.78; PS = 2.10 ± 1.53 / t1: SS = 7.50 ± 9.54; PS = 0.97 ± 1.13). The number of DRPs in this period was significantly reduced as well.
Conclusion
Even a single comprehensive medication review significantly improved medication appropriateness in PwD. Based on the results, pharmacist-led medication reviews are strongly recommended for PwDs
Sacrospinous ligament fixation after failed sacrocolpopexy : a case series
No full textRecurrent apical prolapse after failed sacrocolpopexy poses a surgical challenge, with limited evidence on surgical treatments. This case series evaluates the feasibility and 1-year outcomes of sacrospinous ligament fixation (SSLF) of the residual cervix in this setting. Three postmenopausal women with symptomatic recurrent apical prolapse underwent SSLF after prior laparoscopic sacrocolpopexy. At 3- and 12-month follow-up, all patients showed sustained apical support (POP-Q C −8), with significant improvement in symptoms and quality of life (ICIQ-VS scores). Mild, asymptomatic anterior compartment descent was noted in two cases. SSLF of the cervix appears to be a safe, effective, and minimally invasive alternative to redo sacrocolpopexy for selected patients with recurrent apical prolapse
Elucidating the role of the transcription factor interferon regulatory factor 4 in differentiated T helper 17 and regulatory T cells
No full textV, 137 Seiten ; Illustrationen, Diagramm
Einfluss einer vorherigen Statin-Therapie auf das klinische Outcome nach zerebralem Großgefäßverschluss und mechanischer Thrombektomie
No full text88, XIX Seiten ; Illustrationen, Diagramm
Exploring transcriptomic regulation of the developing brain through integrative bioinformatics and deep learning approaches
Get PDFThe mammalian brain is a remarkably complex organ whose development relies on precise molecular and cellular processes. One of the most sophisticated brain structures is the cerebral cortex. Many proteins and microRNAs play distinct roles in the posttranscriptional regulation of corticogenesis. Mutations in RNA-binding proteins and miRNAs are linked to neurodevelopmental disorders, highlighting their crucial role in central nervous system development.
This doctoral thesis investigates posttranscriptional mechanisms that shape brain development, focusing on alternative splicing and microRNA regulation. Premature overexpression of the RNA binding protein Rbfox2 during murine corticogenesis caused migration and differentiation defects through an altered splicing pattern, likely antagonizing PTBP2’s splicing program. In this study, it was further shown that the neuronal progenitor cell-specific miR-92a-3p repressed Rbfox2 both in vitro and in vivo, revealing a novel regulatory relationship between miRNAs and splicing factors during neural development.
Furthermore, analysis of miRNAs during embryonic corticogenesis revealed clusters of coregulated miRNAs with overlapping target sets. Luciferase assays showed that such cotargeting of miRNAs enhances the repression effect on shared target mRNAs. This finding suggests a complex regulatory network where multiple miRNAs cooperatively fine-tune gene expression during brain development.
To support future research, two computational tools were developed: a web portal (www.cortexa-rna.com) providing access to neocortex/hippocampus RNA-sequencing datasets, improving the accessibility of transcriptomic data to the broader scientific community. Additionally, I implemented a deep learning framework for denoising functional imaging recordings. This computational tool enables the validation of molecular changes in synaptic function at single synapse resolution, bridging the gap between molecular alterations (including splicing-induced changes) and their functional consequences in neurons.182 Seiten ; Illustrationen, Diagramm
Two different perspectives on heatwaves within the Lagrangian framework
Get PDFAlthough heatwaves are one of the most dangerous types of weather-related hazards, their underlying mechanisms are not yet sufficiently understood. In particular, there is still no scientific consensus about the relative importance of the three key processes: horizontal temperature transport, subsidence accompanied by adiabatic heating, and diabatic heating. The current study quantifies these processes using an Eulerian method based on tracer advection, which allows one to extract Lagrangian information. For each grid point at any time, the method yields a decomposition of temperature anomalies into the aforementioned processes, complemented by the contribution of a pre-existing anomaly. Two different approaches for this decomposition are employed. The first approach is based on the full fields of the respective terms and has been established in prior research. In contrast, the second approach is based on the anomaly fields of the respective terms, i.e. deviations from their corresponding climatologies, and