Metabolism and toxicity of two new benzodiazepine-type antileishmanial agents in hepatocytes and macrophages

With increasing reports of resistance of Leishmania to antimonials (Thakur et al., 2004) and other traditional antileishmanial drugs, the need for the discovery of new antileishmanial agents is rising. In an attempt to find new antileishmanial agents, two new benzodiazepine (BNZ) analogues (7-chloro-4-(cyclohexylmethyl)-1-methyl-3,4-dihydro-1H-1,4-benodiazepine-2,5-dione (BNZ-1) and 4-(cyclohexylmethyl)-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (BNZ-2)) were synthesised, and found to be effective against leishmaniasis in mice. This study investigates the metabolism of these two drugs together with the prototype BNZ, flurazepam (FZP), using rat hepatocytes, and investigates their interaction with glutathione in macrophages. Hepatocytes (>80% viability by Trypan Blue exclusion isolated by liver perfusion with collagenase) were prepared from male Sprague-Dawley rats (200-250 g). Drugs (100 μM) were incubated with 2 × 106 viable cells/ml in Krebs-Hepes buffer, pH 7.4, in rotating round bottomed flasks under an atmosphere of 95% O2/5% CO2, at 37 °C for 3 h, and timed samples taken for metabolite measurement. Samples were extracted twice with ethyl acetate at pH 10, the combined organic phases evaporated to dryness and stored at −20 °C until analysis. Metabolites were separated by HPLC using an ACE C18 column (50 mm × 3.0 mm i.d., 5 μm packing), and a solvent gradient consisting of 0.1% formic acid: acetonitrile (starting composition 95:5%, and composition after 25 min 65:35% for FZP and 70:30% for both BNZ 1 and 2). Flow rate was 0.5 ml/min, and detection was at 230 nm. Identification of the metabolites was by mass spectrometry with both positive and negative ion electronspray ionization. The effects of 24 h exposure to the compounds (100 μM) was investigated in the macrophage cell line J774.1 in terms of reduced glutathione content (GSH) and the activity of glutathione reductase (GR). There was no evidence of significant cytotoxicity with any of the compounds at the concentration used. FZP (m/z 388) was metabolised by dealkylation of the two N-1 ethyl substituents (m/z 360 and m/z 332), followed by hydroxylation on the BNZ ring. There was no evidence for either N- or O-glucuronidation of the resulting metabolites. BNZ-1 (m/z 321) was metabolised by N-demethylation (m/z 307) followed by hydroxylation (m/z 323), mono- and di-hydroxylation of the parent (m/z 337 and m/z 353) and by glucuronidation of the mono-hydroxylated metabolite (m/z 513). BNZ-2 (m/z 287) was transformed by N-demethylation (m/z 273) and hydroxylation of the parent (m/z 303), with the latter further metabolised by O-glucuronidation (m/z 479). In addition, the hydroxylated N-demethylated product (m/z 289) was also formed. Macrophages did not produce detectable metabolism of any of the drugs. All the drugs depleted macrophage GSH significantly (p < 0.05 by ANOVA followed by Dunnett's test) with BNZ-1 and BNZ-2 causing greater depletion than FZP (40.6 ± 4.0 and 45.8 ± 8.4, respectively, compared with 55.5 ± 4.9 nmol/mg protein with FZP, n = 3). Control macrophage GSH was 74.1 ± 6.6 nmol/mg protein. The depletion in GSH was not due to inhibition of GR: only FZP caused a significant decrease in macrophage GR activity (28.0 ± 5.9 compared with 42.1 ± 8.0 nmol/ml/min in control cells, p < 0.05 by ANOVA followed by Dunnett's test, n = 3). The marked depletion of macrophage GSH indicates a potential toxic interaction in mammalian cells. The new BNZ analogues were rapidly metabolised by hepatocytes, producing N-dealkylated and multiple hydroxylated phase I metabolites, followed by glucuronidation. This rapid metabolism may limit the therapeutic effect of BNZ 1 and 2 if their metabolites are inactive against leishmaniasis and suggest the need to optimise these lead structures further to obtain compounds with reduced rates and extent of metabolism

The Propagation of Coherent Waves Across Multiple Solar Magnetic Pores

Solar pores are efficient magnetic conduits for propagating magnetohydrodynamic wave energy into the outer regions of the solar atmosphere. Pore observations often contain isolated and/or unconnected structures, preventing the statistical examination of wave activity as a function of the atmospheric height. Here, using high-resolution observations acquired by the Dunn Solar Telescope, we examine photospheric and chromospheric wave signatures from a unique collection of magnetic pores originating from the same decaying sunspot. Wavelet analysis of high-cadence photospheric imaging reveals the ubiquitous presence of slow sausage-mode oscillations, coherent across all photospheric pores through comparisons of intensity and area fluctuations, producing statistically significant in-phase relationships. The universal nature of these waves allowed an investigation of whether the wave activity remained coherent as they propagate. Utilizing bisector Doppler velocity analysis of the Ca ii 8542 Å line, alongside comparisons of the modeled spectral response function, we find fine-scale 5 mHz power amplification as the waves propagate into the chromosphere. Phase angles approaching zero degrees between co-spatial line depths spanning different line depths indicate standing sausage modes following reflection against the transition region boundary. Fourier analysis of chromospheric velocities between neighboring pores reveals the annihilation of the wave coherency observed in the photosphere, with examination of the intensity and velocity signals from individual pores indicating they behave as fractured waveguides, rather than monolithic structures. Importantly, this work highlights that wave morphology with atmospheric height is highly complex, with vast differences observed at chromospheric layers, despite equivalent wave modes being introduced into similar pores in the photosphere

New directions in island biogeography

Aim: Much of our current understanding of ecological and evolutionary processes comes from island research. With the increasing availability of data on distributions and phylogenetic relationships and new analytical approaches to understanding the processes that shape species distributions and interactions, a re-evaluation of this ever-interesting topic is timely. Location: Islands globally. Methods: We start by arguing that the reasons why island research has achieved so much in the past also apply to the future. We then critically assess the current state of island biogeography, focusing on recent changes in emphasis, including research featured in this special issue of Global Ecology and Biogeography. Finally, we suggest promising themes for the future. We cover both ecological and evolutionary topics, although the greater emphasis on island ecology reflects our own backgrounds and interests. Results: Much ecological theory has been directly or indirectly influenced by research on island biotas. Currently, island biogeography is renascent, with research focusing on, among other things, patterns and processes underlying species interaction networks, species coexistence and the assembly of island communities through ecological and evolutionary time. Continuing island research should provide additional insight into biological invasions and other impacts of human activities, functional diversity and ecosystem functioning, extinction and diversification, species pools and more. Deeper understanding of the similarities and differences between island and mainland systems will aid transferability of island theory to continental regions. Main conclusions: As research in biogeography and related fields expands in new directions, islands continue to provide opportunities for developing insights, both as natural laboratories for ecology and evolution and because of the exceptions islands often present to the usual ‘rules’ of ecology. New data collection initiatives are needed on islands world-wide and should be directed towards filling gaps in our knowledge of within-island distributions of species, as well as the functional traits and phylogenetic relationships of island species

Greenhushing: the deliberate under communicating of sustainability practices by tourism businesses

Greenhushing selectively communicates fewer pro-sustainability actions by businesses than are practiced; based on a perception of customers’ rights to consumerism. We first studied the gap between the communication of sustainability practices in the audits and websites of 31 small rural tourism businesses in the Peak District National Park (UK). The analysis showed that businesses only communicate 30% of all the sustainability actions practiced. Their websites emphasised customer benefits, using explicit, affective, experiential and active language that legitimises the customers’ hedonistic use of the landscape, while downplaying complex issues and normalising sustainability to reduce customer guilt. Just one website mentioned climate change. We found that greenhushing results from a low moral intensity, masking potentially negative consequences of perceived lower competence, whilst protecting business from more cynical consumers who may interpret their statements as hypocritical. Subsequent textual analysis and interviews were used to understand how communication constitutes these organisations. We propose that greenhushing reshapes and constitutes tourism businesses through their communications. Moreover, greenhushing is a form of public moralisation that adopts communication practices similar to greenwashing, reflecting the social norms expected from a business; however, in this case, located in a moral muteness, rather than moral hypocrisy, that businesses accept but resent

Solar Wind Turbulence and the Role of Ion Instabilities

International audienc

Roadmap on Li-ion battery manufacturing research

Growth in the Li-ion battery market continues to accelerate, driven primarily by the increasing need for economic energy storage for electric vehicles. Electrode manufacture by slurry casting is the first main step in cell production but much of the manufacturing optimisation is based on trial and error, know-how and individual expertise. Advancing manufacturing science that underpins Li-ion battery electrode production is critical to adding to the electrode manufacturing value chain. Overcoming the current barriers in electrode manufacturing requires advances in materials, manufacturing technology, in-line process metrology and data analytics, and can enable improvements in cell performance, quality, safety and process sustainability. In this roadmap we explore the research opportunities to improve each stage of the electrode manufacturing process, from materials synthesis through to electrode calendering. We highlight the role of new process technology, such as dry processing, and advanced electrode design supported through electrode level, physics-based modelling. Progress in data driven models of electrode manufacturing processes is also considered. We conclude there is a growing need for innovations in process metrology to aid fundamental understanding and to enable feedback control, an opportunity for electrode design to reduce trial and error, and an urgent imperative to improve the sustainability of manufacture

Detector Description and Performance for the First Coincidence Observations between LIGO and GEO

For 17 days in August and September 2002, the LIGO and GEO interferometer gravitational wave detectors were operated in coincidence to produce their first data for scientific analysis. Although the detectors were still far from their design sensitivity levels, the data can be used to place better upper limits on the flux of gravitational waves incident on the earth than previous direct measurements. This paper describes the instruments and the data in some detail, as a companion to analysis papers based on the first data.Comment: 41 pages, 9 figures 17 Sept 03: author list amended, minor editorial change

Community psychiatric nurses and the care co-ordinator role: squeezed to provide ‘limited nursing’.

Background: The Care Programme Approach (CPA) is the key policy underpinning community-focused mental health services but has been unevenly implemented and is associated with increased inpatient bed use. The care co-ordinator role is central to the CPA and is most often held by Community Psychiatric Nurses (CPNs), but there has been little research into how this role is conducted or how it impacts on the work of CPNs and their ability to meet the needs of service users. Aim: The study aimed to identify and illuminate the factors that either facilitated or constrained the ability of CPNs, in their role as care co-ordinators, to meet service users’ and carers’ needs. Methods: A multiple case study of seven sectorised community mental health teams was employed over two years using predominantly qualitative methods of participant observation, semi-structured interviews and document review. Findings: Additional duties and responsibilities specifically associated with the care co-ordinator role and multidisciplinary working, combined with heavy workloads, combined to produce ‘limited nursing’, whereby CPNs are unable to provide evidence-based psychosocial interventions that are recognised to reduce relapse amongst people with severe mental illness. Conclusions: The role of the CPA care co-ordinator was not designed to support the provision of psychosocial interventions. Consequently, CPNs in the co-ordinator role faced with competing demands are unable to provide the range of structured, evidence-based interventions required. This may partially account for the increased inpatient bed use associated with the CPA

Early carboniferous brachiopod faunas from the Baoshan block, west Yunnan, southwest China

38 brachiopod species in 27 genera and subgenera are described from the Yudong Formation in the Shidian-Baoshan area, west Yunnan, southwest China. New taxa include two new subgenera: Unispirifer (Septimispirifer) and Brachythyrina (Longathyrina), and seven new species: Eomarginifera yunnanensis, Marginatia cylindrica, Unispirifer (Unispirifer) xiangshanensis, Unispirifer (Septimispirifer) wafangjieensis, Brachythyrina (Brachythyrina) transversa, Brachythyrina (Longathyrina) baoshanensis, and Girtyella wafangjieensis. Based on the described material and constraints from associated coral and conodont faunas, the age of the brachiopod fauna from the Yudon Formation is considered late Tournaisian (Early Carboniferous), with a possibility extending into earlyViseacutean.<br /

Relevance of the diploma section "Civil protection"

На сьогоднішньому етапі реформування вищої освіти навчальна дисципліна «Цивільний захист» вже не є нормативною і виключена з навчальних планів у вищих навчальних закладах, у тому числі технічного профілю. Але соціально-економічна ситуація в країні, нажаль, ускладнюється. Тому зростає необхідність і важливість питань захисту населення в умовах надзвичайних ситуацій.The discipline "Civil Protection" is not normative any more and excluded from the curriculum in higher educational institutions, including the technical profile at the present stage of reforming higher education. However, unfortunately, the socio-economic situation in the country is becoming more complicated. In these conditions, the need and importance of protecting the population in emergency situations is increasing