Ligneous membranitis in Scottish Terriers is associated with a single nucleotide polymorphism in the plasminogen (PLG) gene

Ligneous membranitis (LM) is a rare chronic inflammatory condition of the mucous membranes associated with plasminogen (encoded by PLG) deficiency in affected humans and dogs. In human, the condition is genetic in nature with numerous mutations and polymorphisms in PLG identified in affected individuals and related family members. The condition is uncommonly reported in dogs and, to date, no genetic studies have been performed. We identified related Scottish Terriers (littermates) with severe LM and unaffected relatives (sire, dam and a sibling from a previous litter). Plasma plasminogen activity was below normal in one affected dog but within normal reference intervals for the other. Sequencing of PLG from the affected dogs revealed a homozygous A>T single nucleotide polymorphism in an intron donor site (c.1256+2T>A). The related, unaffected dogs displayed heterozygous alleles at this position (c.1256+2T/A), whereas no mutation was detected in unaffected, non‐related control dogs. This is the first report to identify gene polymorphisms associated with LM in dogs.     

Something for the weekend? Examining the bias in avian phenological recording

In this paper we examine the bias towards weekend recording (the weekend effect) in volunteer phenology, using over 14,000 bird migration phenological observations from eight locations in the UK as a data source. Data from 45 bird species were used. Overall, 44% of all records were taken at weekends in contrast to the 28.6% (i.e. two out of seven days) that would be expected if records were evenly spread throughout the week. Whilst there is documented evidence of environmental differences at weekends, particularly in large urban areas, we believe the weekend effect is mostly a consequence of greater recorder effort at weekends. Some birds, likely to be obvious by their behaviour or abundance, had fewer weekend records than the remaining species. The weekend effect, to some extent, differed between locations and between seasons. There was some evidence that, particularly in autumn, the weekend bias may be lessening. If so, this will increase the accuracy of phenological records, making the detection of changes and responses to temperature easier.     

Combined Psychophysiological Assessment of ADHD: A Pilot Study of Bayesian Probability Approach Illustrated by Appraisal of ADHD in Female College Students

Manifestations of ADHD are observed at both psychological and physiological levels and assessed via various psychometric, EEG, and imaging tests. However, no test is 100% accurate in its assessment of ADHD. This study introduces a stochastic assessment combining psychometric tests with previously reported (Consistency Index) and newly developed (Alpha Blockade Index) EEG-based physiological markers of ADHD. The assessment utilizes classical Bayesian inference to refine after each step the probability of ADHD of each individual. In a pilot study involving six college females with ADHD and six matched controls, the assessment achieved correct classification for all ADHD and non-ADHD participants. In comparison, the classification of ADHD versus non-ADHD participants was < 85% for any one of the tests separately. The procedure significantly improved the score separation between ADHD versus non-ADHD groups. The final average probabilities for ADHD were 76% for the ADHD group and 8% for the control group. These probabilities correlated (r = .87) with the Brown ADD scale and (r = .84) with the ADHD-Symptom Inventory used for the screening of the participants. We conclude that, although each separate test was not completely accurate, a combination of several tests classified correctly all ADHD and all non-ADHD participants. The application of the proposed assessment is not limited to the specific tests used in this study--the assessment represents a general paradigm capable of accommodating a variety of ADHD tests into a single diagnostic assessment.     

Fast and effective: intense pulse light photodynamic inactivation of bacteria

The goal of this study was to investigate the photodynamic toxicity of TMPyP (5, 10, 15, 20-Tetrakis (1-methylpyridinium-4-yl)-porphyrin tetra p-toluenesulfonate) in combination with short pulses (ms) of an intense pulse light source within 10 s against Bacillus atrophaeus, Staphylococcus aureus, Methicillin-resistant S. aureus and Escherichia coli, major pathogens in food industry and in health care, respectively. Bacteria were incubated with a photoactive dye (TMPyP) that is subsequently irradiated with visible light flashes of 100 ms to induce oxidative damage immediately by generation of reactive oxygen species like singlet oxygen. A photodynamic killing efficacy of up to 6 log(10) (>99.9999%) was achieved within a total treatment time of 10 s using a concentration range of 1-100 μmol TMPyP and multiple light flashes of 100 ms (from 20 J cm(-2) up to 80 J cm(-2)). Both incubation of bacteria with TMPyP alone or application of light flashes only did not have any negative effect on bacteria survival. Here we could demonstrate for the first time that the combination of TMPyP as the respective photosensitizer and a light flash of 100 ms of an intense pulsed light source is enough to generate sufficient amounts of reactive oxygen species to kill these pathogens within a few seconds. Increasing antibiotic resistance requires fast and efficient new approaches to kill bacteria, therefore the photodynamic process seems to be a promising tool for disinfection of horizontal surfaces in industry and clinical purposes where savings in time is a critical point to achieve efficient inactivation of microorganisms.     

Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1

As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a K_d value of 22 nM and a biochemical IC₅₀ of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1.     

L protease from foot and mouth disease virus confers eIF2-independent translation for mRNAs bearing picornavirus IRES

The leader protease (L^pro) from foot-and-mouth disease virus (FMDV) has the ability to cleave eIF4G, leading to a blockade of cellular protein synthesis. In contrast to previous reports, our present findings demonstrate that FMDV L^pro is able to increase translation driven by FMDV IRES. Additionally, inactivation of eIF2 subsequent to phosphorylation induced by arsenite or thapsigargin in BHK cells blocks protein synthesis directed by FMDV IRES, whereas in the presence of L^pro, significant translation is found under these conditions. This phenomenon was also observed in cell-free systems after induction of eIF2 phosphorylation by addition of poly(I:C).     

Emergent Global Patterns of Ecosystem Structure and Function from a Mechanistic General Ecosystem Model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures.     

Functional Characterization of a Novel Family of Acetylcholine-Gated Chloride Channels in Schistosoma mansoni

Acetylcholine is the canonical excitatory neurotransmitter of the mammalian neuromuscular system. However, in the trematode parasite Schistosoma mansoni, cholinergic stimulation leads to muscle relaxation and a flaccid paralysis, suggesting an inhibitory mode of action. Information about the pharmacological mechanism of this inhibition is lacking. Here, we used a combination of techniques to assess the role of cholinergic receptors in schistosome motor function. The neuromuscular effects of acetylcholine are typically mediated by gated cation channels of the nicotinic receptor (nAChR) family. Bioinformatics analyses identified numerous nAChR subunits in the S. mansoni genome but, interestingly, nearly half of these subunits carried a motif normally associated with chloride-selectivity. These putative schistosome acetylcholine-gated chloride channels (SmACCs) are evolutionarily divergent from those of nematodes and form a unique clade within the larger family of nAChRs. Pharmacological and RNA interference (RNAi) behavioral screens were used to assess the role of the SmACCs in larval motor function. Treatment with antagonists produced the same effect as RNAi suppression of SmACCs; both led to a hypermotile phenotype consistent with abrogation of an inhibitory neuromuscular mediator. Antibodies were then generated against two of the SmACCs for use in immunolocalization studies. SmACC-1 and SmACC-2 localize to regions of the peripheral nervous system that innervate the body wall muscles, yet neither appears to be expressed directly on the musculature. One gene, SmACC-1, was expressed in HEK-293 cells and characterized using an iodide flux assay. The results indicate that SmACC-1 formed a functional homomeric chloride channel and was activated selectively by a panel of cholinergic agonists. The results described in this study identify a novel clade of nicotinic chloride channels that act as inhibitory modulators of schistosome neuromuscular function. Additionally, the iodide flux assay used to characterize SmACC-1 represents a new high-throughput tool for drug screening against these unique parasite ion channels.     

The design and synthesis of indazole and pyrazolopyridine based glucokinase activators for the treatment of Type 2 diabetes mellitus

Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.     

Extent of invasion of Tasmanian native vegetation by the exotic bumblebee Bombus terrestris (Apoidea: Apidae)

Abstract Observations of the large earth bumblebee, Bombus terrestris (L.), in native vegetation were collated to determine the extent to which this exotic species has invaded Tasmanian native vegetation during the first 9 years after its introduction. The range of B. terrestris now encompasses all of Tasmania's major vegetation types, altitudes from sea level to 1260m a.s.L, and the entire breadth of annual precipitation in the state from more than 3200 mm to less than 600 mm. Observations of workers carrying pollen, together with the presence of large numbers of bumblebees at many localities across this range indicate that colonies are frequently established in native vegetation. Evidence that colonies are often successful was obtained from repeated observations of the species during more than 1 year at particular sites. Unequivocal evidence of colonies was obtained from six National Parks, including four of the five in the Tasmanian Wilderness World Heritage Area (WHA). Indeed, the species has been present in the WHA for at least as long as it has in the city of Hobart, where it was first recorded. In southwestern Tasmania, evidence of colonies was obtained up to 40km from gardens, 61 km from small towns and 93 km from large towns. Hence, contrary to previous suggestions, the species is established in the most remote parts of Tasmania and is not dependent on introduced garden plants. Given their strong record of invasion, it is likely that B. terrestris will form feral populations on the mainland of Australia and in many other parts of the world if introduced. Because of their likely negative impacts on native animals and plants, and potential to enhance seed production in weeds, the spread of bumblebees should be avoided.