Recreational use, analysis and toxicity of tryptamines

The definition New psychoactive substances (NPS) refers to emerging drugs whose chemical structures are similar to other psychoactive compounds but not identical, representing a "legal" alternative to internationally controlled drugs. There are many categories of NPS, such as synthetic cannabinoids, synthetic cathinones, phenylethylamines, piperazines, ketamine derivatives and tryptamines. Tryptamines are naturally occurring compounds, which can derive from the amino acid tryptophan by several biosynthetic pathways: their structure is a combination of a benzene ring and a pyrrole ring, with the addition of a 2-carbon side chain. Tryptamines include serotonin and melatonin as well as other compounds known for their hallucinogenic properties, such as psilocybin in 'Magic mushrooms' and dimethyltryptamine (DMT) in Ayahuasca brews

Spontaneous Synchronization in Two Mutually Coupled Memristor-Based Chua’s Circuits: Numerical Investigations

Chaotic dynamics of numerous memristor-based circuits is widely reported in literature. Recently, some works have appeared which study the problem of synchronization control of these systems in a master-slave configuration. In the present paper, the spontaneous dynamic behavior of two chaotic memristor-based Chua’s circuits, mutually interacting through a coupling resistance, was studied via computer simulations in order to study possible self-organized synchronization phenomena. The used memristor is a flux controlled memristor with a cubic nonlinearity, and it can be regarded as a time-varying memductance. The memristor, in effect, retains memory of its past dynamic and any difference in the initial conditions of the two circuits results in different values of the corresponding memductances. In this sense, due to the memory effect of the memristor, even if coupled circuits have the same parameters they do not constitute two completely identical chaotic oscillators. As is known, for nonidentical chaotic systems, in addition to complete synchronizations (CS) other weaker forms of synchronization which provide correlations between the signals of the two systems can also occur. Depending on initial conditions and coupling strength, both chaotic and nonchaotic synchronization are observed for the system considered in this work

Development and validation of a GC-MS method for the detection and quantification of clotiapine in blood and urine specimens and application to a postmortem case

INTRODUCTION: Clotiapine is an atypical antipsychotic of the dibenzothiazepine class introduced in a few European countries since 1970, efficient in treatment-resistant schizophrenic patients. There is little published data on the therapeutic and toxic concentrations of this drug. AIMS: The aim of the present study is the development and validation of a method that allows the detection and quantification of clotiapine in blood and urine specimens by gas chromatography-mass spectrometry (GC-MS). METHODS: Validation was performed working on spiked postmortem blood and urine samples. Samples were extracted with liquid-liquid extraction (LLE) technique at pH 8.5 with n-hexane/dichloromethane (85/15 v/v) and analysis was followed by GC-MS. Methadone-d9 was used as internal standard. RESULTS: The limit of detection (LOD) was 1.2 and 1.3 ng/mL for urine and blood, respectively, while the lower limit of quantification (LLOQ) was 3.9 and 4.3 ng/mL, respectively. Linearity, precision, selectivity, accuracy, and recovery were also determined. The method was applied to a postmortem case. The blood and urine clotiapine concentrations were 1.32 and 0.49 μg/mL, respectively. CONCLUSIONS: A reliable GC-MS method for the detection and quantification of clotiapine in blood and urine samples has been developed and fully validated and then applied to a postmortem case

Neurotoxicity induced by mephedrone: an up-to-date review

BACKGROUND: Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. OBJECTIVE: The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. MATERIALS AND METHODS: Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc.) using the keywords: "Mephedrone", "4-MMC," "neurotoxicity," "neuropharmacology", "patents", "monoamine transporters" and "neurochemical effects". RESULTS: Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-hydroxytryptamine (5-HT) and dopamine (DA) systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function. Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the design of the experiments, including temperature and animal model used, the results are difficult to compare. CONCLUSIONS: Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public health

Cues to opening mechanisms from in silico electric field excitation of cx26 hemichannel and in vitro mutagenesis studies in HeLa transfectans

Connexin channels play numerous essential roles in virtually every organ by mediating solute exchange between adjacent cells, or between cytoplasm and extracellular milieu. Our understanding of the structure-function relationship of connexin channels relies on X-ray crystallographic data for human connexin 26 (hCx26) intercellular gap junction channels. Comparison of experimental data and molecular dynamics simulations suggests that the published structures represent neither fully-open nor closed configurations. To facilitate the search for alternative stable configurations, we developed a coarse grained (CG) molecular model of the hCx26 hemichannel and studied its responses to external electric fields. When challenged by a field of 0.06 V/nm, the hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second transmembrane helix (TM2) at the level of the conserved Pro87. A point mutation that inhibited such transition in our simulations impeded hemichannel opening in electrophysiology and dye uptake experiments conducted on HeLa tranfectants. These results suggest that the hCx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among the whole connexin family

The development and application of an optimization tool in industrial design

AbstractDesigners are identified, in industry 4.0, as the professional figures that have to design well performing new object. In order to do this, it is necessary to take into account a series of properties called design objectives. Often the structural problem of new design is underestimated or even not considered. This can be a real problem because this objective is in competitive and in contrast with other design objectives. So, this can bring to substantial change in a design in the final phase and sometimes to the complete change. In this paper is presented an optimization workflow that adopt a Multi Objective Optimization engine so called "Octopus" and Karamba3D, that is a Finite Elements (FE) plug-in, typically used in structural simulations, these extensions run in a software: Grassopper3D, that is a parametric design tool. The workflow allows designers to explore a large range of solutions and at the same time permits to filter and sort the optimized models in order to analyze the tradeoff of the resultant solution space, both qualitatively and quantitatively. In such way designers can obtain easily a lot of information of the generate design and identify potential solution for immediate use or for further optimization. In this paper is analyzed a design problem of an ergonomic chair in order to provide the efficiency of the workflow. The design criteria and the structural problem for this type of design object are identified as the main optimization objectives in order to iteratively improve the design solutions

Corticobasal syndrome: neuroimaging and neurophysiological advances

Corticobasal degeneration (CBD) is a neurodegenerative condition characterized by 4R-tau protein deposition in several brain regions that clinically manifests itself as a heterogeneous atypical parkinsonism typically expressing in the adulthood. The prototypical clinical phenotype of CBD is corticobasal syndrome (CBS). Important insights into the pathophysiological mechanisms underlying motor and higher cortical symptoms in CBS have been gained by using advanced neuroimaging and neurophysiological techniques. Structural and functional neuroimaging studies often showed asymmetric cortical and subcortical abnormalities, mainly involving perirolandic and parietal regions and basal ganglia structures. Neurophysiological investigations including electroencephalography and somatosensory evoked potentials provided useful information on the origin of myoclonus and on cortical sensory loss. Transcranial magnetic stimulation demonstrated heterogeneous and asymmetric changes in the excitability and plasticity of primary motor cortex and abnormal hemispheric connectivity. Neuroimaging and neurophysiological abnormalities in multiple brain areas reflect the asymmetric neurodegeneration, leading to the asymmetric motor and higher cortical symptoms in CBS. This article is protected by copyright. All rights reserved

New Concept in Bioderived Composites: Biochar as Toughening Agent for Improving Performances and Durability of Agave-Based Epoxy Biocomposites

Biocomposites are increasingly used in the industry for the replacement of synthetic materials, thanks to their good mechanical properties, being lightweight, and having low cost. Unfortunately, in several potential fields of structural application their static strength and fatigue life are not high enough. For this reason, several chemical treatments on the fibers have been proposed in literature, although still without fully satisfactory results. To overcome this drawback, in this study we present a procedure based on the addition of a carbonaceous filler to a green epoxy matrix reinforced by Agave sisalana fibers. Among all carbon-based materials, biochar was selected for its environmental friendliness, along with its ability to improve the mechanical properties of polymers. Different percentages of biochar, 1, 2, and 4 wt %, were finely dispersed into the resin using a mixer and a sonicator, then a compression molding process coupled with an optimized thermomechanical cure process was used to produce a short fiber biocomposite with Vf = 35%. Systematic experimental tests have shown that the presence of biochar, in the amount 2 wt %, has significant effects on the matrix and fiber interphase, and leads to an increase of up to three orders of magnitude in the fatigue life, together with an appreciable improvement in static tensile strength

Wavefront invasion for a chemotaxis model of Multiple Sclerosis

In this work we study wavefront propagation for a chemotaxis reaction-diffusion system describing the demyelination in Multiple Sclerosis. Through a weakly non linear analysis, we obtain the Ginzburg–Landau equation governing the evolution of the amplitude of the pattern. We validate the analytical findings through numerical simulations. We show the existence of traveling wavefronts connecting two different steady solutions of the equations. The proposed model reproduces the progression of the disease as a wave: for values of the chemotactic parameter below threshold, the wave leaves behind a homogeneous plaque of apoptotic oligodendrocytes. For values of the chemotactic coefficient above threshold, the model reproduces the formation of propagating concentric rings of demyelinated zones, typical of Baló’s sclerosis

A new bioinformatic pipeline allows the design of small, targeted gene panels for efficient TMB estimation

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