Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects

Antipsychotic drugs have various neuropharmacological properties as a result of their structural diversity. Despite their therapeutic benefits, most of the prescribed atypical antipsychotics can induce severe side effects, including weight gain, type II diabetes mellitus, and cardiovascular diseases. Among the developed atypical antipsychotic agents, tetracyclic dibenzodiazepine and thienobenzodiazepine compounds, particularly clozapine and olanzapine, are associated with the greatest weight gain and metabolic disturbances. However, the unique chemical structure of these compounds causes the low risk of side effects reported for typical antipsychotics (e.g. extrapyramidal symptoms and tardive dyskinesia). This report reviews the recent discovery of the potential role of the chemical structure of antipsychotics in their therapeutic properties and metabolic disturbances. By developing structure-activity relationship studies for atypical antipsychotics, we will improve our understanding of the structural modifications of these chemical classes that lead to reduced weight gain, which will be an invaluable step toward the discovery of the next generation of atypical antipsychotics. In this review, we suggest that a novel dibenzodiazepine or thienobenzodiazepine antipsychotic drug with lower affinity for H(1) receptors may significantly advance schizophrenia therapy.     

Response of Strawberry Plant cv. ‘Camarosa’ to Salicylic Acid and Methyl Jasmonate Application Under Salt Stress Condition

The possible role of salicylic acid (SA) and methyl jasmonate (MJ) treatments on the physiology responses and growth of strawberry (Fragaria?×?ananassa) cv. ‘Camarosa’ subjected to the different levels of salinity stress were investigated. Root and shoot growth as well as their Na⁺/K⁺ ratio, photosynthetic-related factors, and activity of some important antioxidant enzymes were determined in the salt-treated plants. Results indicated that salt stress reduced plant performance especially at higher concentrations. By increasing the levels of salinity stress, fresh and dry weight of shoot and roots, net photosynthetic rate (Pn), and stomatal conductance (Gs) significantly decreased, whereas intercellular CO₂ (Ci) increased. Application of exogenous SA and MJ significantly improved the plant physiological characters as well as fresh and dry weight of shoots and roots. Moreover, the ratio of Na⁺/K⁺ was elevated in the leaves and roots concomitantly with salinity levels, whereas SA and MJ treatments significantly reduced this ratio. Results of enzymatic assays showed that activity of ascorbate peroxidase, peroxidase, and superoxide dismutase enzymes increased in the salt-stressed plants. In addition, SA and MJ treatments reduced the destructive effects of salinity in strawberry plant. In general, among the tested concentrations, 0.5 mM SA and 0.25 mM MJ best increased the activity of antioxidant enzymes and hence alleviated the detrimental effects of salinity stress.     

Optimizing MRI sequences and images for MRI-based stereotactic radiosurgery treatment planning

AimDevelopment of MRI sequences and processing methods for the production of images appropriate for direct use in stereotactic radiosurgery (SRS) treatment planning.BackgroundMRI is useful in SRS treatment planning, especially for patients with brain lesions or anatomical targets that are poorly distinguished by CT, but its use requires further refinement. This methodology seeks to optimize MRI sequences to generate distortion-free and clinically relevant MR images for MRI-only SRS treatment planning.Materials and methodsWe used commercially available SRS MRI-guided radiotherapy phantoms and eight patients to optimize sequences for patient imaging. Workflow involved the choice of correct MRI sequence(s), optimization of the sequence parameters, evaluation of image quality (artifact free and clinically relevant), measurement of geometrical distortion, and evaluation of the accuracy of our offline correction algorithm.ResultsCT images showed a maximum deviation of 1.3 mm and minimum deviation of 0.4 mm from true fiducial position for SRS coordinate definition. Interestingly, uncorrected MR images showed maximum deviation of 1.2 mm and minimum of 0.4 mm, comparable to CT images used for SRS coordinate definition. After geometrical correction, we observed a maximum deviation of 1.1 mm and minimum deviation of only 0.3 mm.ConclusionOur optimized MRI pulse sequences and image correction technique show promising results; MR images produced under these conditions are appropriate for direct use in SRS treatment planning.     

Electron‐Beam‐Evaporated Nickel Oxide Hole Transport Layers for Perovskite‐Based Photovoltaics

High‐quality charge carrier transport materials are of key importance for stable and efficient perovskite‐based photovoltaics. This work reports on electron‐beam‐evaporated nickel oxide (NiO_x) layers, resulting in stable power conversion efficiencies (PCEs) of up to 18.5% when integrated into solar cells employing inkjet‐printed perovskite absorbers. By adding oxygen as a process gas and optimizing the layer thickness, transparent and efficient NiO_x hole transport layers (HTLs) are fabricated, exhibiting an average absorptance of only 1%. The versatility of the material is demonstrated for different absorber compositions and deposition techniques. As another highlight of this work, all‐evaporated perovskite solar cells employing an inorganic NiO_x HTL are presented, achieving stable PCEs of up to 15.4%. Along with good PCEs, devices with electron‐beam‐evaporated NiO_x show improved stability under realistic operating conditions with negligible degradation after 40 h of maximum power point tracking at 75 °C. Additionally, a strong improvement in device stability under ultraviolet radiation is found if compared to conventional perovskite solar cell architectures employing other metal oxide charge transport layers (e.g., titanium dioxide). Finally, an all‐evaporated perovskite solar mini‐module with a NiO_x HTL is presented, reaching a PCE of 12.4% on an active device area of 2.3 cm².     

Molecular phylogeny of the subterranean genus Niphargus (Crustacea: Amphipoda) in the Middle East: a comparison with European Niphargids

The subterranean genus Niphargus is one of the most species‐rich genera among freshwater amphipods in the world, distributed in the Western Palearctic. Thus far, taxonomic and phylogenetic research has focused mainly on the European half of the genus range. In this study, 25 populations of Niphargus from Iran, Lebanon and the Crimean Peninsula were investigated. Bayesian inference based on 28S, H3 and COI gene sequences suggests that populations from the area belong to four different clades. Three species from Crimea and one species from Iran are nested at basal nodes, indicating their rather ancient origin. The rest of the species are younger and belong to two separate clades. One Crimean species is a sister‐species to east Romanian species. The second clade includes one species from Lebanon and all but one population from Iran. The origin of this clade corresponds to marine transgression between the Black Sea and Mediterranean approximately 12 Mya. This clade was further investigated taxonomically. Revision of qualitative morphological traits and unilocus species delimitation methods using COI suggest that this clade comprises 12–16 species, of which only three have been described so far. Multilocus coalescence delimitation methods (using fragments of COI, 28S, H3 and ITS) strongly supported 11 of these species. The remaining populations comprise at least two species complexes that require further and more detailed taxonomic research. © 2015 The Linnean Society of London     

Flower ontogeny in Capparis spinosa (Capparaceae) with special emphasis on symmetry expression

The flower ontogeny of Capparis spinosa L. was studied using scanning electron microscopy (SEM) in order to shed light on the early expression of symmetry in a representative member of Capparaceae. Sepals start decussately with the abaxial and adaxial sepals, followed by the lateral ones. Petal appearance proceeds uni‐directionally from the abaxial to the adaxial side. Stamens develop centrifugally on an androecial ring. Five to seven carpel lobes arise on a gynoecial ring. Monosymmetry is established in early development by the uni‐directional petal appearance and is further enhanced by the acquisition of an abaxial nectary appendage and differential development of perianth organs at anthesis. The early monosymmetric pattern found in C. spinosa differs from the early monosymmetric and early disymmetric pathways of Cleomoideae. Our findings are consistent with the hypothesis that the late establishment of monosymmetry is a reflective of symmetry in early development.     

The stereoselective metabolism of halofantrine to desbutylhalofantrine in the rat: evidence of tissue-specific enantioselectivity in microsomal metabolism

The pharmacokinetics of the antimalarial drug (+/-)-halofantrine are stereoselective in humans and rats. To better understand the stereoselective metabolism of the drug to its primary metabolite, desbutylhalofantrine (DHF), a series of in vitro and in vivo experiments were undertaken in the rat. Formation of (-)-DHF exceeded that of (+)-DHF in liver microsomes [(-):(+) ratio of intrinsic formation clearances = 1.4]. In contrast, in intestinal microsomes no significant stereoselectivity was noted in the formation of the DHF enantiomers. Intestinal microsomes were also less efficient at producing the DHF enantiomers than were liver microsomes. Based on kinetic analysis of the DHF formation, there appeared to be more than one enzyme involved in the biotransformation. (+/-)-Ketoconazole (KTZ) effectively inhibited the formation of both DHF enantiomers by both liver and intestinal microsomes, although the reduction was more marked in liver microsomes. Through a combination of the use of CYP antibodies and recombinant CYP isoenzymes, the involvement of CYP 2B1/2, 3A1, 3A2, 1A1, 2C11, 2C6, 2D1, and 2D2 were implicated in the metabolism of halofantrine to DHF. Of these, CYP3A1/2 and CYP2C11 appeared to be the primary isoenzymes involved, although CYP2C11 showed greater (+)-DHF than (-)-DHF formation, whereas for CYP3A1 it was similar to the isolated rat liver microsomes. In vivo, oral (+/-)-KTZ caused significant increases in plasma halofantrine and decreases in DHF enantiomer plasma concentrations.