Pteridine-2,4-diamine derivatives as radical scavengers and inhibitors of lipoxygenase that can possess anti-inflammatory properties

BACKGROUND: Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. The complex nature of inflammation and of oxidative stress suggests that dual-target agents may be effective in combating diseases involving reactive oxygen species. RESULTS: A novel series of N-substituted 2,4-diaminopteridines has been synthesized and evaluated as antioxidants in several assays. Many exhibited potent lipid antioxidant properties, and some are inhibitors of soybean lipoxygenase, IC50 values extending down to 100 nM for both targets. Several pteridine derivatives showed efficacy at 0.01 mmol/kg with little tissue damage in a rat model of colitis. 2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)pteridin-4-amine (18f) at 0.01 mmol/kg exhibited potent anti-inflammatory activity (reduction by 41%). CONCLUSION: The 2,4-diaminopteridine core represents a new scaffold for lipoxygenase inhibition as well as sustaining anti-inflammatory properties

Impact of socioeconomic deprivation on rate and cause of death in severe mental illness

Background: Socioeconomic status has important associations with disease-specific mortality in the general population. Although individuals with Severe Mental Illnesses (SMI) experience significant premature mortality, the relationship between socioeconomic status and mortality in this group remains under investigated.<p></p> Aims: To assess the impact of socioeconomic status on rate and cause of death in individuals with SMI (schizophrenia and bipolar disorder) relative to the local (Glasgow) and wider (Scottish) populations.<p></p> Methods: Cause and age of death during 2006-2010 inclusive for individuals with schizophrenia or bipolar disorder registered on the Glasgow Psychosis Clinical Information System (PsyCIS) were obtained by linkage to the Scottish General Register Office (GRO). Rate and cause of death by socioeconomic status, measured by Scottish Index of Multiple Deprivation (SIMD), were compared to the Glasgow and Scottish populations.<p></p> Results: Death rates were higher in people with SMI across all socioeconomic quintiles compared to the Glasgow and Scottish populations, and persisted when suicide was excluded. Differences were largest in the most deprived quintile (794.6 per 10,000 population vs. 274.7 and 252.4 for Glasgow and Scotland respectively). Cause of death varied by socioeconomic status. For those living in the most deprived quintile, higher drug-related deaths occurred in those with SMI compared to local Glasgow and wider Scottish population rates (12.3% vs. 5.9%, p = <0.001 and 5.1% p = 0.002 respectively). A lower proportion of deaths due to cancer in those with SMI living in the most deprived quintile were also observed, relative to the local Glasgow and wider Scottish populations (12.3% vs. 25.1% p = 0.013 and 26.3% p = <0.001). The proportion of suicides was significantly higher in those with SMI living in the more affluent quintiles relative to Glasgow and Scotland (54.6% vs. 5.8%, p = <0.001 and 5.5%, p = <0.001). Discussion and conclusions: Excess mortality in those with SMI occurred across all socioeconomic quintiles compared to the Glasgow and Scottish populations but was most marked in the most deprived quintiles when suicide was excluded as a cause of death. Further work assessing the impact of socioeconomic status on specific causes of premature mortality in SMI is needed

In-silico investigation of Coenzyme A selectivity for Aurora A kinase and development of an Aurora A kinase-selective inhibitor as a potential anticancer agent

Centrosome amplification has been observed in most cancer cells, and is considered to be a “hallmark” of cancer cells. This process is commonly associated with chromosome segregation process in the mitosis phase in the cell cycle, which is tightly controlled by mitotic kinases. Among these kinases, the Aurora kinase family, Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), ensures the accurate progression of mitosis, including the formation of a bipolar mitotic spindle, accurate segregation of chromosomes and the completion of cytokinesis. AURKA has been seen to have the largest role in mitotic progression and checkpoint control pathways and overexpression of AURKA is most associated with cancer. Hence, interfering with AURKA activity has been considered to be a promising approach to anticancer agents. Professor Gout’s group has recently shown that Coenzyme A (CoA) selectively inhibits AURKA activity (IC50 of 4.4 μM). However, its large molecular weight (>500) and negatively charged phosphate group make it unsuitable as a drug candidate. This project was set to investigate the possible binding modes of CoA in the catalytic domain of AURKA. The corresponding interactions between CoA and protein residues would provide some insights in the selectivity of CoA towards AURKA. Furthermore, based on the understanding of the interactions between CoA and the catalytic domain of AURKA and the possible reasons behind the selectivity of CoA towards AURKA, in silico design and synthesis of a new highly selective and potent AURKA inhibitor based on the structure of CoA and current lead compounds which are in clinical trials for Aurora kinase inhibitors could be carried out

Location of chlorogenic acid biosynthesis pathway and polyphenol oxidase genes in a new interspecific anchored linkage map of eggplant

© Gramazio et al.; licensee BioMed Central. 2014. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Efl teachers’ facebook groups as online communities of practice: toward configurations for engagement and sustainability

The emergence of online communities has redefined teachers’ professional development. Voluntary participation in online teacher communities offers possibilities for problemsolving, reflective thinking, knowledge exchanging, and social emotion sharing. However, little research has been conducted about the quality and depth of interactions among EFL teachers while participating in online communities. In response to the call for rigorous research featuring the roles of online communities on teacher learning beyond the Western contexts and the realities of participants’ contribution, this case study analyzed two Facebook groups of Vietnamese EFL teachers using Wenger’s (1998) analytical framework for communities of practice (CoP). Facebook groups were adopted as an online CoP platform because of its widespread social media penetration in Vietnam-with users being 75% of the population (Nguyen, 2019). Adopting a multiple-site case study design, the study surveyed 84 teachers and analyzed the content of selected posts and comments in two Facebook groups in five months, focusing on members’ engagement, perceived benefits, and recommendations regarding their CoP participation. Findings illustrate different realities of university lecturers and school teachers within the two Facebook groups in lights of knowledge domains, sharing practice, and moderation activity. The paper offers insights for the design and administration of online CoP in social media spaces

Glycans as receptors for influenza pathogenesis

Influenza A viruses, members of the Orthomyxoviridae family, are responsible for annual seasonal influenza epidemics and occasional global pandemics. The binding of viral coat glycoprotein hemagglutinin (HA) to sialylated glycan receptors on host epithelial cells is the critical initial step in the infection and transmission of these viruses. Scientists believe that a switch in the binding specificity of HA from Neu5Acα2-3Gal linked (α2-3) to Neu5Acα2-6Gal linked (α2-6) glycans is essential for the crossover of the viruses from avian to human hosts. However, studies have shown that the classification of glycan binding preference of HA based on sialic acid linkage alone is insufficient to establish a correlation between receptor specificity of HA and the efficient transmission of influenza A viruses. A recent study reported extensive diversity in the structure and composition of α2-6 glycans (which goes beyond the sialic acid linkage) in human upper respiratory epithelia and identified different glycan structural topologies. Biochemical examination of the multivalent HA binding to these diverse sialylated glycan structures also demonstrated that high affinity binding of HA to α2-6 glycans with a characteristic umbrella-like structural topology is critical for efficient human adaptation and human-human transmission of influenza A viruses. This review summarizes studies which suggest a new paradigm for understanding the role of the structure of sialylated glycan receptors in influenza virus pathogenesis.National Institute of General Medical Sciences (U.S.) (Glue Grant U54 GM62116)National Institutes of Health (U.S.) (Grant GM57073)Singapore-MIT Alliance for Research and Technolog

Differential branching fraction and angular analysis of Λb0→Λμ+μ−\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^- decays

The differential branching fraction of the rare decay $\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-$ is measured as a function of $q^{2}$, the square of the dimuon invariant mass. The analysis is performed using proton-proton collision data, corresponding to an integrated luminosity of 3.0 \mbox{ fb}^{-1}, collected by the LHCb experiment. Evidence of signal is observed in the $q^2$ region below the square of the $J/\psi$ mass. Integrating over 15 < q^{2} < 20 \mbox{ GeV}^2/c^4 the branching fraction is measured as d\mathcal{B}(\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-)/dq^2 = (1.18 ^{+ 0.09} _{-0.08} \pm 0.03 \pm 0.27) \times 10^{-7} ( \mbox{GeV}^{2}/c^{4})^{-1}, where the uncertainties are statistical, systematic and due to the normalisation mode, $\Lambda^{0}_{b} \rightarrow J/\psi \Lambda$, respectively. In the $q^2$ intervals where the signal is observed, angular distributions are studied and the forward-backward asymmetries in the dimuon ($A^{l}_{\rm FB}$) and hadron ($A^{h}_{\rm FB}$) systems are measured for the first time. In the range 15 < q^2 < 20 \mbox{ GeV}^2/c^4 they are found to be A^{l}_{\rm FB} = -0.05 \pm 0.09 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)} and A^{h}_{\rm FB} = -0.29 \pm 0.07 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)}.Comment: 27 pages, 10 figures, Erratum adde

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV

Linking a dermal permeation and an inhalation model to a simple pharmacokinetic model to study airborne exposure to di(n-butyl) phthalate

Six males clad only in shorts were exposed to high levels of airborne di(n-butyl) phthalate (DnBP) and diethyl phthalate (DEP) in chamber experiments conducted in 2014. In two 6 h sessions, the subjects were exposed only dermally while breathing clean air from a hood, and both dermally and via inhalation when exposed without a hood. Full urine samples were taken before, during, and for 48 h after leaving the chamber and measured for key DnBP and DEP metabolites. The data clearly demonstrated high levels of DnBP and DEP metabolite excretions while in the chamber and during the first 24 h once leaving the chamber under both conditions. The data for DnBP were used in a modeling exercise linking dose models for inhalation and transdermal permeation with a simple pharmacokinetic model that predicted timing and mass of metabolite excretions. These models were developed and calibrated independent of these experiments. Tests included modeling of the “hood-on” (transdermal penetration only), “hood-off” (both inhalation and transdermal) scenarios, and a derived “inhalation-only” scenario. Results showed that the linked model tended to duplicate the pattern of excretion with regard to timing of peaks, decline of concentrations over time, and the ratio of DnBP metabolites. However, the transdermal model tended to overpredict penetration of DnBP such that predictions of metabolite excretions were between 1.1 and 4.5 times higher than the cumulative excretion of DnBP metabolites over the 54 h of the simulation. A similar overprediction was not seen for the “inhalation-only” simulations. Possible explanations and model refinements for these overpredictions are discussed. In a demonstration of the linked model designed to characterize general population exposures to typical airborne indoor concentrations of DnBP in the United States, it was estimated that up to one-quarter of total exposures could be due to inhalation and dermal uptake

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns