Three data mining techniques to improve lazy structure-activity relationships for non-congeneric compounds

We present three simple, yet effective data mining techniques for lazy structure-activity relationships (SARs) of noncongeneric compounds. In lazy SARs, classifications are particularly tailored for each test compound. Therefore, it is possible to make the most of the structure of a test compound. In our case, we derive its substructures and use them to determine similar structures. To obtain a well-balanced and representative set of structural descriptors, we enrich this set by strongly activating or deactivating fragments from the training set and subsequently remove redundant fragments. Finally, we perform k-Nearest Neighbor classification for several values of k and take a vote among the resulting predictions. These technique (enrichment, removing redundancy, and voting) are integrated into the system iSAR (instance-based structure-activity relationships) and tested individually to show the relative contribution to the system’s performance. Experiments on three data sets indicate that this simple and lightweight approach performs at least on the same level as other, more complex approaches

Near-Infrared (NIR) Spectrometry as a Fast and Reliable Tool for Fat and Moisture Analyses in Olives

The evaluation of fat and moisture contents for olive fruits is crucial for both olive growers and olive oil processors. Reference methods, such as Soxhlet extraction, used for fat content determination in olive fruits are time- and solvent- consuming and labor intensive. Near-infrared (NIR) spectroscopy is proposed as a solution toward rapid and nondestructive analyses of olive fruit fat and moisture contents. In the present work, comparative studies of the fat and moisture quantification methods were performed on four cultivars (Arbosana, Arbequina, Chiquitita, and Koroneiki) during six different harvesting time points to determine the potential of NIR as an alternative methodology. The impact of olive paste crushing degree on NIR performance was also investigated using three different grid sizes (4, 6, and 8 mm) on a hammer mill, in addition to a blade crusher. Results indicate a satisfactory correlation between the reference Soxhlet and NIR methods with R 2 = 0.995. A comparison study of moisture content was also done on NIR and the use of conventional oven with the R 2 value of 0.995. The crushing blade produced higher values in both moisture and fat contents in comparison to the hammer mill. The evaluation indicates that when building a chemometric model, all crush sizes and blade sizes should be represented in the model for highest accuracy

Visualization of the Breakdown of the Axonal Transport Machinery: a Comparative Ultrastructural and Immunohistochemical Approach

Axonal damage is a major factor contributing to disease progression in multiple sclerosis (MS) patients. On the histological level, acute axonal injury is most frequently analyzed by anti-amyloid precursor protein immunohistochemistry. To what extent this method truly detects axonal injury, and whether other proteins and organelles are as well subjected to axonal transport deficits in demyelinated tissues is not known. The aim of this study was to correlate ultrastructural morphology with the immunohistochemical appearance of acute axonal injury in a model of toxin-induced oligodendrocyte degeneration. C57BL/6J mice were intoxicated with 0.25% cuprizone to induce demyelination. The corpus callosum was investigated by serial block-face scanning electron microscopy (i.e., 3D EM), immunohistochemistry, and immunofluorescence microscopy. Brain tissues of progressive MS patients were included to test the relevance of our findings in mice for MS. Volumes of axonal swellings, determined by 3D EM, were comparable to volumes of axonal spheroids, determined by anti-APP immunofluorescence stains. Axonal swellings were present at myelinated and non-myelinated axonal internodes. Densities of amyloid precursor protein (APP)+ spheroids were highest during active demyelination. Besides APP, vesicular glutamate transporter 1 and mitochondrial proteins accumulated at sites of axonal spheroids. Such accumulations were found as well in lesions of progressive MS patients. In this correlative ultrastructural-immunohistochemical study, we provide strong evidence that breakdown of the axonal transport machinery results in focal accumulations of mitochondria and different synaptic proteins. We provide new marker proteins to visualize acute axonal injury, which helps to further understand the complex nature of axonal damage in progressive MS

The Novel Psychoactive Substance Cumyl-CH-MEGACLONE: Human Phase-I Metabolism, Basic Pharmacological Characterization, and Comparison to Other Synthetic Cannabinoid Receptor Agonists with a γ-Carboline-1-one Core

Synthetic cannabinoids (SC) remain one of the largest groups of new psychoactive substances on the European drug market. In December 2018, Cumyl-CH-MEGACLONE, a novel SC based on a gamma-carboline-1-one core structure, was firstly identified in Hungary and later also other European countries. This work aims to reveal the pharmacological characteristics and phase-1 metabolism of Cumyl-CH-MEGACLONE and compare the data to its analogs Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE. The purified substance was characterized by means of gas chromatography-mass spectrometry (GC-MS), liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QToF-MS), attenuated total reflection infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance spectroscopy. Phase-1 metabolites were identified by LC-QToF-MS analysis combined with a scheduled precursor ion list of authentic urine samples and confirmed by comparison with metabolites built in vitro by pooled human liver microsome assays. Pharmacological data were obtained in a competitive ligand binding assay and a receptor activation assay at the human cannabinoid receptor 1 (hCB(1)). The structure of 5-cyclohexylmethyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (semisystematic name: Cumyl-CH-MEGACLONE) was identified in a herbal blend as the main active ingredient. Investigation of phase-I biotransformation of Cumyl-CH-MEGACLONE led to three monohydroxylated metabolites (M08, M10 and M13) as reliable urinary markers for proof of consumption. At the hCB(1), Cumyl-CH-MEGACLONE shows high binding affinity with K-i = 1.01 nM (2.5-fold higher than JWH-018), an EC50 of 1.22 nM and high efficacy with E-MAX = 143.4% above constitutive activity of the receptor (1.13-fold higher than JWH-018). Comparison to the analogs 5F-Cumyl-PEGACLONE and Cumyl-PEGACLONE (both are hCB(1) full agonists carrying a 5-fluoropentyl or pentyl chain instead of the cyclohexylmethyl moiety) suggests that Cumyl-CH-MEGACLONE is more likely to resemble the pharmacologic profile of the latter one