The misuse of fentanyl, and novel synthetic opioids (NSO) in general, has become a public health emergency, especially in the United States. The detection of NSO is often challenged by the limited diagnostic time frame allowed by urine sampling and the wide range of chemically modified analogues, continuously introduced to the recreational drug market. In this study, an untargeted metabolomics approach was developed to obtain a comprehensive “fingerprint” of any anomalous and specific metabolic pattern potentially related to fentanyl exposure. In recent years, in vitro models of drug metabolism have emerged as important tools to overcome the limited access to positive urine samples and uncertainties related to the substances actually taken, the possible combined drug intake, and the ingested dose. In this study, an in vivo experiment was designed by incubating HepG2 cell lines with either fentanyl or common drugs of abuse, creating a cohort of 96 samples. These samples, together with 81 urine samples including negative controls and positive samples obtained from recent users of either fentanyl or “traditional” drugs, were subjected to untargeted analysis using both UHPLC reverse phase and HILIC chromatography combined with QTOF mass spectrometry. Data independent acquisition was performed by SWATH in order to obtain a comprehensive profile of the urinary metabolome. After extensive processing, the resulting datasets were initially subjected to unsupervised exploration by principal component analysis (PCA), yielding clear separation of the fentanyl positive samples with respect to both controls and samples positive to other drugs. The urine datasets were then systematically investigated by supervised classification models based on soft independent modeling by class analogy (SIMCA) algorithms, with the end goal of identifying fentanyl users. A final single-class SIMCA model based on an RP dataset and five PCs yielded 96% sensitivity and 74% specificity. The distinguishable metabolic patterns produced by fentanyl in comparison to other opioids opens up new perspectives in the interpretation of the biological activity of fentanyl. 相似文献
Herein, we report the synthesis of a series of heteroleptic magnesium complexes stabilized with the scorpionate ligand tris(2-pyridylthio)methanide (Tptm). The compounds of the general formula [Mg(Tptm)(X)] (1-X; X = Cl, Br, I) were obtained via protonolysis reaction between the proligand and selected Grignard reagents. Attempts to isolate the potassium derivative K(Tptm) lead to decomposition of Tptm and formation of the alkene (C5H4N-S)2C=C(C5H4N-S)2, and this degradation was also modelled using DFT methods. Compound 1-I was treated with K(CH2Ph), affording the degradation product [Mg(Bptm)2] (2; Bptm = {CH(S-C5NH3)2}−). We analyzed and quantified the steric properties of the Tptm ligand using the structural information of the compounds obtained in this study paired with buried volume calculations, also adding the structural data of HTptm and its CF3-substituted congener (HTptmCF3). These studies highlight the highly flexible nature of this ligand scaffold and its ability to stabilize various coordination motifs and geometries, which is a highly desirable feature in the design of novel organometallic reagents and catalysts. 相似文献
Mycobacterial pathogens are intrinsically resistant to many available antibiotics, making treatment extremely challenging, especially in immunocompromised individuals and patients with underlying and chronic lung conditions. Even with lengthy therapy and the use of a combination of antibiotics, clinical success for non-tuberculous mycobacteria (NTM) is achieved in fewer than half of the cases. The need for novel antibiotics that are effective against NTM is urgent. To identify such new compounds, a whole cell high-throughput screen (HTS) was performed in this study. Compounds from the Chembridge DIVERSet library were tested for their ability to inhibit intracellular survival of M. avium subsp. hominissuis (MAH) expressing dtTomato protein, using fluorescence as a readout. Fifty-eight compounds were identified to significantly inhibit fluorescent readings of MAH. In subsequent assays, it was found that treatment of MAH-infected THP-1 macrophages with 27 of 58 hit compounds led to a significant reduction in intracellular viable bacteria, while 19 compounds decreased M. abscessus subsp. abscessus (Mab) survival rates within phagocytic cells. In addition, the hit compounds were tested in M. tuberculosis H37Ra (Mtb) and 14 compounds were found to exhibit activity in activated THP-1 cells. While the majority of compounds displayed inhibitory activity against both replicating (extracellular) and non-replicating (intracellular) forms of bacteria, a set of compounds appeared to be effective exclusively against intracellular bacteria. The efficacy of these compounds was examined in combination with current antibiotics and survival of both NTM and Mtb were evaluated within phagocytic cells. In time-kill dynamic studies, it was found that co-treatment promoted increased bacterial clearance when compared with the antibiotic or compound group alone. This study describes promising anti-NTM and anti-Mtb compounds with potential novel mechanisms of action that target intracellular bacteria in activated macrophages. 相似文献
The control of crystal formation has been developed to a remarkable degree by many organisms. Oriented nucleation, control over crystal morphology, formation of unique composites of proteins and single crystals, and the production of ordered multicrystal arrays, are all well within the realm of biological capability. Understanding the control and design principles in biomineralization is a fascinating subject that may well contribute to the improved fabrication of synthetic materials on the one hand, and to the solution of many serious pathological problems involving mineralization, on the other. 相似文献
In the chitons (Polyplacophora, Mollusca), the body is not entirely protected by the shell. Mineralized spicules or scales often, but not always, decorate the exposed part of the girdle. Here, we report a study on the composition and ultrastructural organization of these mineralized skeletal parts in four different chiton species. In all specimens, the mineral component (97–98 wt‐%) is aragonite, and the organic matrix (2–3 wt‐%) consists of highly glycosylated proteins. X‐Ray diffraction and scanning electron microscopy show that the organic matrix fibers are aligned, morphologically and crystallographically, with the prismatic aragonite crystals. Matrix and mineral are thus clearly related. The matrix–mineral composite bundles are, however, assembled in the various skeletal parts examined with widely different degrees of alignment and order. In the same organism, the crystals are aligned within a range of ±15° in one type of spicule, while they are randomly oriented in another type. The wide heterogeneity in shape, density, and ultrastructure suggests that the girdle mineralized tissues do not fulfill a fundamental role necessary for the survival of the organism. This, together with the lack of chitin in the organic matrix, supports the hypothesis that they evolved separately from the other chiton mineralized tissues, namely the shell plates and teeth. 相似文献
Two types of unsupported zeolites (silicalite-1 and silicalite-2) and porous alumina discs supports were prepared by the hydrothermal sol–gel synthesis method. The influence of the raw materials used as SiO2 source, the temperature of the thermal treatment and the presence of the ceramic support on the crystallization of zeolites were studied. The reaction products were characterized by X-ray diffraction (XRD), IR spectroscopy (IR) and scanning electron microscopy (SEM) studies. The SiO2 source had a significant effect on the final zeolite obtained: the use of colloidal silica sol (ZCS) as SiO2 source in the synthesis led to ZSM-11 (silicalite-2) crystals, while the sodium silicate solution (ZSS) produced the ZSM-5 (silicalite-1) type. The presence of the alumina support influences the crystallization process of ZSM-5, as it improves nucleation and the ordering of the crystals. 相似文献
An integrated multisensor composed by six ISFET devices selective to common ions and heavy metals combined with a flow injection analysis (FIA) system has been applied as an electronic tongue to grape juice and wine sample analysis. The data obtained for several grape and wine variety samples analysis have been treated using multiparametric tools like principal component analysis (PCA) and soft independent modelling class analogy technique (SIMCA) for the patterning recognition and classification of samples and partial least squares (PLS) regression for quantification of several parameters of interest in wine production. The results obtained have demonstrated the potential of using those multisensors as electronic tongues not only for distinguishing the samples according to the grape variety and the vintage year but also for quantitative prediction of several sample parameters. 相似文献
This paper considers an integrated approach to two common problems in a precision agriculture framework: management zone delineation and selective harvest scheduling. Our model minimizes the total costs of harvest operations, establishing planning and scheduling for selective harvest of each selected management zone. Therefore, this tool provides important information for decision making of farmers in the field. Our integrated model is contrasted with the hierarchical approach commonly used in the literature for these cases, where the result of zoning problem is an input to schedule the harvest problem. Both problems were solved through a complete enumeration of all the potential management zones and demonstrated the advantages of our proposed model over the hierarchical approach. Our model reached an average reduction of 10% in harvest operations costs for different instances in a case study.