Effect of spatial variation on salinity tolerance of macroinvertebrates in Eastern Australia and implications for ecosystem protection trigger values

Salinisation of freshwater has been identified as a serious environmental issue in Australia and around the world. Protective concentrations (trigger values) for salinity can be used to manage salinity impacts, though require locally relevant salinity tolerance information. 72-h acute salinity tolerance values were determined for 102 macroinvertebrates collected from 11 locations in four biologically distinct freshwater bio-regions in Northeast Australia and compared with sensitivities observed in Southeast Australia. The salinity tolerance of individual taxa was consistent across Northeast Australia and between Northeast and Southeast Australia. However, two distinct communities were identified in Northeast Australia using distributions of the acute tolerance values and a calculated index of salinity sensitivity. Salinity trigger values should therefore be representative of local or regionally relevant communities and may be adequately calculated using sensitivity values from throughout Eastern Australia. The results presented provide a basis for assessing salinity risk and determining trigger values for salinity in freshwater ecosystems at local and regional scales in Eastern Australia. Crown Copyrigh

Population pharmacokinetics of NNZ-2566 in healthy subjects

NNZ-2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile-X syndrome, both of which are associated with moderate to severe neurodevelopmental disorder. In current study we characterise the population pharmacokinetics of NNZ-2566 after administration of single and repeated ascending doses to healthy subjects. A meta-analytical approach was used to analyse pharmacokinetic data from 3 different studies, in which a total of 61 healthy subjects (median age 23years, range 19 to 38) were treated with NNZ-2566. Doses of NNZ-2566 ranged from 6.0 to 100mg/kg after oral administration and from 0.1 to 30mg/kg after intravenous administration. A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of NNZ-2566. Inter-individual variability was identified in clearance, absorption rate, central volume of distribution, peripheral volume of distribution and inter-compartmental clearance. Population predicted clearance and central volume of distribution were 10.35L/h and 20.23L, respectively. No accumulation, metabolic inhibition or induction was observed during the course of treatment. Dose proportionality was observed across the dose range evaluated in healthy subjects. In addition, oral bioavailability appeared to vary with food intake. The relatively short half-life of 1.4h suggests the need for a twice or three times daily regimen to maintain relevant systemic levels of NNZ-2566 in plasma

A Phase 2 Study of AMO-02 (tideglusib) in Congenital and Childhood Onset Myotonic Dystrophy Type 1 (DM1)

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM1), a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of DM1 and promotes cellular maturation as well as normalizing aberrant molecular and behavioral phenotypes. This Phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy, of AMO-02 in adolescents and adults with Congenital and Childhood-onset DM1. Methods: Sixteen subjects (aged 13 to 34) with Congenital and Childhood-onset DM1 received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n=8) or 1000 mg (n=8) of AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and ECGs, as well as efficacy assessments of syndromal, cognitive and muscular functioning, were obtained. Results: AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area-under-the-curve, or AUC) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events nor dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their CNS and neuromuscular symptoms after 12 weeks of treatment compared to the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative AUC) was significantly correlated (p<0.01) with change from baseline on several key efficacy assessments. Conclusion: AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for Congenital and Childhood-onset DM1

Simulated Optimisation of Disordered Structures with negative Poisson’s ratios

Copyright © 2009 Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in Mechanics of Materials. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Mechanics of Materials, Vol. 41 Issue 8 (2009). DOI: 10.1016/j.mechmat.2009.04.008Two-dimensional regular theoretical units that give a negative Poisson’s ratio (NPR) are well documented and well understood. Predicted mechanical properties resulting from these models are reasonably accurate in two dimensions but fall down when used for heterogeneous real-world materials. Manufacturing processes are seldom perfect and some measure of heterogeneity is therefore required to account for the deviations from the regular unit cells in this real-life situation. Analysis of heterogeneous materials in three dimensions is a formidable problem; we must first understand heterogeneity in two dimensions. This paper approaches the problem of finding a link between heterogeneous networks and its material properties from a new angle. Existing optimisation tools are used to create random two-dimensional topologies that display NPR, and the disorder in the structure and its relationship with NPR is investigated

Reciprocity as a foundation of financial economics

This paper argues that the subsistence of the fundamental theorem of contemporary financial mathematics is the ethical concept ‘reciprocity’. The argument is based on identifying an equivalence between the contemporary, and ostensibly ‘value neutral’, Fundamental Theory of Asset Pricing with theories of mathematical probability that emerged in the seventeenth century in the context of the ethical assessment of commercial contracts in a framework of Aristotelian ethics. This observation, the main claim of the paper, is justified on the basis of results from the Ultimatum Game and is analysed within a framework of Pragmatic philosophy. The analysis leads to the explanatory hypothesis that markets are centres of communicative action with reciprocity as a rule of discourse. The purpose of the paper is to reorientate financial economics to emphasise the objectives of cooperation and social cohesion and to this end, we offer specific policy advice

Integrated Genomic Analysis Implicates Haploinsufficiency of Multiple Chromosome 5q31.2 Genes in De Novo Myelodysplastic Syndromes Pathogenesis

Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS). Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow) and germline (skin) DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion) and performed total exonic gene resequencing (479 amplicons) and array comparative genomic hybridization (CGH). We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50% in CD34+ cells from del(5q) MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion

Agroecology and Health: Lessons from Indigenous Populations.

Purpose of reviewThe article aims to systematize and disseminate the main contributions of indigenous ancestral wisdom in the agroecological production of food, especially in Latin America. For this purpose, it is necessary to ask whether such knowledge can be accepted by academia research groups and international forums as a valid alternative that could contribute to overcome the world's nutritional problems.Recent findingsAlthough no new findings are being made, the validity of ancestral knowledge and agroecology is recognized by scientific research, and by international forums organized by agencies of the United Nations. These recommend that governments should implement them in their policies of development, and in the allocation of funds to support these initiatives. Agroecology and ancestral knowledge are being adopted by a growing number of organizations, indigenous peoples and social groups in various parts of the world, as development alternatives that respond to local needs and worldviews. Its productive potential is progressively being recognized at an international level as a model that contributes to improve the condition of people regarding nutritional food

The Caenorhabditis elegans Gene mfap-1 Encodes a Nuclear Protein That Affects Alternative Splicing

RNA splicing is a major regulatory mechanism for controlling eukaryotic gene expression. By generating various splice isoforms from a single pre–mRNA, alternative splicing plays a key role in promoting the evolving complexity of metazoans. Numerous splicing factors have been identified. However, the in vivo functions of many splicing factors remain to be understood. In vivo studies are essential for understanding the molecular mechanisms of RNA splicing and the biology of numerous RNA splicing-related diseases. We previously isolated a Caenorhabditis elegans mutant defective in an essential gene from a genetic screen for suppressors of the rubberband Unc phenotype of unc-93(e1500) animals. This mutant contains missense mutations in two adjacent codons of the C. elegans microfibrillar-associated protein 1 gene mfap-1. mfap-1(n4564 n5214) suppresses the Unc phenotypes of different rubberband Unc mutants in a pattern similar to that of mutations in the splicing factor genes uaf-1 (the C. elegans U2AF large subunit gene) and sfa-1 (the C. elegans SF1/BBP gene). We used the endogenous gene tos-1 as a reporter for splicing and detected increased intron 1 retention and exon 3 skipping of tos-1 transcripts in mfap-1(n4564 n5214) animals. Using a yeast two-hybrid screen, we isolated splicing factors as potential MFAP-1 interactors. Our studies indicate that C. elegans mfap-1 encodes a splicing factor that can affect alternative splicing.National Natural Science Foundation (China) (Grant 30971639)United States. National Institutes of Health (Grant GM24663

Voltage-Dependent Gating in a “Voltage Sensor-Less” Ion Channel

An unusual mechanism of ion channel regulation generates voltage-dependent gating in the absence of a canonical voltage-sensing domain

Fluorescence-Tracking of Activation Gating in Human ERG Channels Reveals Rapid S4 Movement and Slow Pore Opening

Background: hERG channels are physiologically important ion channels which mediate cardiac repolarization as a result of their unusual gating properties. These are very slow activation compared with other mammalian voltage-gated potassium channels, and extremely rapid inactivation. The mechanism of slow activation is not well understood and is investigated here using fluorescence as a direct measure of S4 movement and pore opening. Methods and Findings: Tetramethylrhodamine-5-maleimide (TMRM) fluorescence at E519 has been used to track S4 voltage sensor movement, and channel opening and closing in hERG channels. Endogenous cysteines (C445 and C449) in the S1–S2 linker bound TMRM, which caused a 10 mV hyperpolarization of the VK of activation to 227.562.0 mV, and showed voltage-dependent fluorescence signals. Substitution of S1–S2 linker cysteines with valines allowed unobstructed recording of S3–S4 linker E519C and L520C emission signals. Depolarization of E519C channels caused rapid initial fluorescence quenching, fit with a double Boltzmann relationship, F-VON, with VK,1 = 237.861.7 mV, and VK,2 = 43.567.9 mV. The first phase, VK,1, was,20 mV negative to the conductance-voltage relationship measured from ionic tail currents (G-VK = 218.361.2 mV), and relatively unchanged in a non-inactivating E519C:S620T mutant (V K = 234.461.5 mV), suggesting the fast initial fluorescence quenching tracked S4 voltage sensor movement. The second phase of rapid quenching was absent in the S620T mutant. The E519C fluorescence upon repolarizatio