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431.
JodiAnne T. Wood Dustin M. Smith David R. Janero Alexander M. Zvonok Alexandros Makriyannis 《Life sciences》2013,92(8-9):482-491
AimsAM-1241, a novel, racemic cannabinoid-2 receptor (CB2) ligand, is the primary experimental agonist used to characterize the role of CB2-mediated lipid signaling in health and disease, including substance abuse disorders. In vivo pharmacological effects have been used as indirect proxies for AM-1241 biotransformation processes that could modulate CB2 activity. We report the initial pre-clinical characterization of AM-1241 biotransformation and in vivo distribution.Main methodsAM-1241 metabolism was characterized in a variety of predictive in vitro systems (Caco-2 cells; mouse, rat and human microsomes) and in the mouse in vivo. Liquid chromatography and mass spectrometry techniques were used to quantify AM-1241 tissue distribution and metabolic conversion.Key findingsAM-1241 bound extensively to plasma protein/albumin. A pharmacological AM-1241 dose (25 mg/kg, i.v.) was administered to mice for direct determination of its plasma half-life (37 min), following which AM-1241 was quantified in brain, spleen, liver, and kidney. After p.o. administration, AM-1241 was detected in plasma, spleen, and kidney; its oral bioavailability was ~ 21%. From Caco-2 permeability studies and microsomal-based hepatic clearance estimates, in vivo AM-1241 absorption was moderate. Hepatic microsomal metabolism of AM-1241 in vitro generated hydroxylation and demethylation metabolites. Species-dependent differences were discovered in AM-1241's predicted hepatic clearance. Our data demonstrate that AM-1241 has the following characteristics: a) short plasma half-life; b) limited oral bioavailability; c) extensive plasma/albumin binding; d) metabolic substrate for hepatic hydroxylation and demethylation; e) moderate hepatic clearance.SignificanceThese results should help inform the design, optimization, and pre-clinical profiling of CB2 ligands as pharmacological tools and medicines. 相似文献
432.
Gkitsaki Ioanna Papachristoforou Alexandros Michailidou Sofia Karamvalis Nikolaos Iliadis Ioannis Graikini Dimitra Sakarikou Christina Tsoukis Evangelos Argyriou Anagnostis Giaouris Efstathios 《International microbiology》2023,26(3):691-691
International Microbiology - 相似文献
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Oskar L. P. Hansen Jens‐Christian Svenning Kent Olsen Steen Dupont Beulah H. Garner Alexandros Iosifidis Benjamin W. Price Toke T. Hye 《Ecology and evolution》2020,10(2):737-747
- Changes in insect biomass, abundance, and diversity are challenging to track at sufficient spatial, temporal, and taxonomic resolution. Camera traps can capture habitus images of ground‐dwelling insects. However, currently sampling involves manually detecting and identifying specimens. Here, we test whether a convolutional neural network (CNN) can classify habitus images of ground beetles to species level, and estimate how correct classification relates to body size, number of species inside genera, and species identity.
- We created an image database of 65,841 museum specimens comprising 361 carabid beetle species from the British Isles and fine‐tuned the parameters of a pretrained CNN from a training dataset. By summing up class confidence values within genus, tribe, and subfamily and setting a confidence threshold, we trade‐off between classification accuracy, precision, and recall and taxonomic resolution.
- The CNN classified 51.9% of 19,164 test images correctly to species level and 74.9% to genus level. Average classification recall on species level was 50.7%. Applying a threshold of 0.5 increased the average classification recall to 74.6% at the expense of taxonomic resolution. Higher top value from the output layer and larger sized species were more often classified correctly, as were images of species in genera with few species.
- Fine‐tuning enabled us to classify images with a high mean recall for the whole test dataset to species or higher taxonomic levels, however, with high variability. This indicates that some species are more difficult to identify because of properties such as their body size or the number of related species.
- Together, species‐level image classification of arthropods from museum collections and ecological monitoring can substantially increase the amount of occurrence data that can feasibly be collected. These tools thus provide new opportunities in understanding and predicting ecological responses to environmental change.
436.
Markus Peschke Mélanie Le Goff Gregory M. Koningstein Alexandros Karyolaimos Jan-Willem de Gier Peter van Ulsen Joen Luirink 《Journal of molecular biology》2018,430(3):389-403
Tail-anchored membrane proteins (TAMPs) are relatively simple membrane proteins characterized by a single transmembrane domain (TMD) at their C-terminus. Consequently, the hydrophobic TMD, which acts as a subcellular targeting signal, emerges from the ribosome only after termination of translation precluding canonical co-translational targeting and membrane insertion. In contrast to the well-studied eukaryotic TAMPs, surprisingly little is known about the cellular components that facilitate the biogenesis of bacterial TAMPs. In this study, we identify DjlC and Flk as bona fide Escherichia coli TAMPs and show that their TMDs are necessary and sufficient for authentic membrane targeting of the fluorescent reporter mNeonGreen. Using strains conditional for the expression of known E. coli membrane targeting and insertion factors, we demonstrate that the signal recognition particle (SRP), its receptor FtsY, the chaperone DnaK and insertase YidC are each required for efficient membrane localization of both TAMPs. A close association between the TMD of DjlC and Flk with both the Ffh subunit of SRP and YidC was confirmed by site-directed in vivo photo-crosslinking. In addition, our data suggest that the hydrophobicity of the TMD correlates with the dependency on SRP for efficient targeting. 相似文献
437.
Fotios Alexandros Karakostis Ian J. Wallace 《American journal of physical anthropology》2023,181(1):130-139
Objectives
When studying hominin skeletal remains, anthropologists commonly assume that the morphology of entheses (muscle and tendon attachment sites) is influenced by physical activity patterns during life. Here, we use samples of mice from a prior experiment (Siegel & Jones [1975] American Journal of Physical Anthropology 42:141–144) to test this assumption. Specifically, we investigate the effects of habitual climbing on entheses of the humerus using a recently developed protocol for analyzing entheseal morphology called the “Validated Entheses-based Reconstruction of Activity” (VERA) method.Materials and Methods
In the original experiment, young mice were raised for approximately 9 weeks in one of two experimental conditions: a cage designed to limit locomotion to terrestrial quadrupedalism over a flat surface (n = 22), or a cage designed to impel animals to cling to a suspended wire mesh apparatus and limit their locomotion to climbing (n = 21). We μCT-scanned the humeri of these mice and used the VERA method to assess the morphology of the deltoid tuberosity, greater tubercle, lesser tubercle, and supinator crest.Results
Significant differences in entheseal morphology were detected between climbers and non-climbers when using both multivariate statistics to assess all entheses simultaneously and univariate statistics to assess each enthesis individually.Discussion
Our results provide new support for the general use of entheseal morphology for inferring hominin physical activity patterns in the past. Furthermore, based on our results, we propose that analyzing entheseal morphology using the VERA method may be a promising strategy for future research on the importance of climbing in hominin locomotor evolution.438.
Alexandros Bousios 《Journal of theoretical biology》2010,264(2):205-210
Retrotransposons occur in extremely large numbers in many eukaryotic genomes. However, little is known of the factors which affect the distribution of close proximity elements. In this work we investigate the frequency of close facing retrotransposons in a plant species with extremely high numbers of retrotransposons. Molecular observations are compared with predictions of a mathematical model that assumes a uniform probability of retrotransposon insertion into the genome. The mathematical model plays the role of a null hypothesis. We find that compared with the predictions of the model, there is a statistically significant deficit of identical copies of facing retroelements that are close to one another. This suggests that an efficient mechanism exists that removes or limits close facing retroelements. 相似文献
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