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The naturally occurring nucleotide 2-deoxy-adenosine 5'-triphosphate (dATP) can be used by cardiac muscle as an alternative energy substrate for myosin chemomechanical activity. We and others have previously shown that dATP increases contractile force in normal hearts and models of depressed systolic function, but the structural basis of these effects has remained unresolved. In this work, we combine multiple techniques to provide structural and functional information at the angstrom-nanometer and millisecond time scales, demonstrating the ability to make both structural measurements and quantitative kinetic estimates of weak actin-myosin interactions that underpin sarcomere dynamics. Exploiting dATP as a molecular probe, we assess how small changes in myosin structure translate to electrostatic-based changes in sarcomere function to augment contractility in cardiac muscle. Through Brownian dynamics simulation and computational structural analysis, we found that deoxy-hydrolysis products [2-deoxy-adenosine 5'-diphosphate (dADP) and inorganic phosphate (Pi)] bound to prepowerstroke myosin induce an allosteric restructuring of the actin-binding surface on myosin to increase the rate of cross-bridge formation. We then show experimentally that this predicted effect translates into increased electrostatic interactions between actin and cardiac myosin in vitro. Finally, using small-angle X-ray diffraction analysis of sarcomere structure, we demonstrate that the proposed increased electrostatic affinity of myosin for actin causes a disruption of the resting conformation of myosin motors, resulting in their repositioning toward the thin filament before activation. The dATP-mediated structural alterations in myosin reported here may provide insight into an improved criterion for the design or selection of small molecules to be developed as therapeutic agents to treat systolic dysfunction.

This paper reports on experiences of Indigenous students and staff involved in Bond Indigenous Tutoring (BIT). It aimed to gain insight regarding topics including challenges faced by Indigenous students, why some students discontinued their studies, and concepts of success at university. Findings revealed the main challenges included the transition from secondary to tertiary education and not being prepared academically. BIT staff identified family responsibilities and being dislocated from kinship networks as challenges, while students stated these were factors explaining why Indigenous students discontinued their studies. A whole of university approach was found to be required to effectively support Indigenous students. Success was defined as more than Grade Point Average, as it entailed being able to enjoy future endeavours. This paper contributes to the evidence that tuition programmes and Indigenous centres at university are key contributors to success, and it is argued that such success must become the norm as opposed to the exception.

Termination of protein synthesis occurs when a translating ribosome encounters one of three universally conserved stop codons: UAA, UAG or UGA. Release factors recognize stop codons in the ribosomal A-site to mediate release of the nascent chain and recycling of the ribosome. Bacteria decode stop codons using two separate release factors with differing specificities for the second and third bases (1). By contrast, eukaryotes rely on an evolutionarily unrelated omnipotent release factor (eRF1) to recognize all three stop codons (2). The molecular basis of eRF1 discrimination for stop codons over sense codons is not known. Here we present cryoelectron microscopy (cryo-EM) structures at 3.5-3.8 Å resolution of mammalian ribosomal complexes containing eRF1 interacting with each of the three stop codons in the A-site. Binding of eRF1 flips nucleotide A1825 of 18S ribosomal RNA so that it stacks on the second and third stop codon bases. This configuration pulls the fourth position base into the A-site, where it is stabilized by stacking against G626 of 18S rRNA. Thus, eRF1 exploits two rRNA nucleotides also used during transfer RNA selection to drive messenger RNA compaction. In this compacted mRNA conformation, stop codons are favoured by a hydrogen-bonding network formed between rRNA and essential eRF1 residues that constrains the identity of the bases. These results provide a molecular framework for eukaryotic stop codon recognition and have implications for future studies on the mechanisms of canonical and premature translation termination (3,4)., Termination of translation in eukaryotes is initiated when a ternary complex of eRF1-eRF3-GTP binds to a stop codon in the ribosomal A-site (5,6). GTP hydrolysis by eRF3 induces a conformational [...]

The goal of natural resource damage assessment (NRDA) is to compensate the public for losses to natural resources from past or ongoing hazardous releases, including losses that may persist into the future. Compensation is delivered in the form of restoration projects. Resolving NRDA liability requires balancing losses and restoration benefits over multiple decades and converting them into a present value for calculating appropriate damages. For the past two decades, NRDA practitioners have used a real discount rate of 3 % to convert losses and benefits to a present value equivalent. That rate was based, in part, on real historical yields on risk-free debt (e.g., the real rate of return on 3-month Treasury bills). Declining interest rates on risk-free debt in recent years has led to suggestions to reexamine the historical consensus discount rate. This paper reviews two alternative conceptual paradigms for selecting a discount rate in NRDA cases: the social rate of time preference and discount rates for tort cases. We summarize historical data for empirically implementing the two paradigms and discuss the ramifications of the different options. Based on our review, we suggest maintaining the 3 % consensus as a practical solution to a range of empirical candidates within the two conceptual paradigms. [ABSTRACT FROM AUTHOR]

Dam removal is a potential habitat restoration alternative through which parties responsible for injuries to natural resources can provide compensation for reductions in fish populations. Predicting the potential response of migratory fish populations to candidate dam removal(s) is a critical step in the natural resource damage assessment process to evaluate whether the proposed action provides adequate compensation. There is currently no standard approach to making such predictions, particularly in cases where data on candidate streams with dams are limited. We considered six modeling approaches for addressing this problem and evaluated the features of each approach for this application. We judged that an approach based on habitat suitability indices and weighted usable area provides the best balance between predictive capacity and cost of model implementation. This balancing act evaluating the cost effectiveness of predictive models is worth consideration in a wide range of fisheries modeling applications. [ABSTRACT FROM AUTHOR]

Purpose Vasopressin is used to maintain blood pressure in vasodilatory shock. Vasopressin is diluted from concentrated vials prior to administration as a continuous infusion. This study evaluates the physical and chemical stability changes of vasopressin diluted to 0.2 units/mL with 0.9% sodium chloride injection in polyvinyl chloride (PVC) bags stored under refrigeration. Methods Vasopressin Injection, USP, 20 unit/mL solution was diluted to 0.2 unit/mL with 0.9% sodium chloride injection, and stability changes were evaluated over 10 days via mass spectrometry on days 0, 7, and 10. Results Solutions of vasopressin 0.2 unit/mL in 0.9% sodium chloride injection in PVC bags were physically stable and showed less than 10% degradation over 10 days of refrigerated storage. Conclusion Vasopressin 0.2 unit/mL may be given a beyond-use date (BUD) of 10 days based on United States Pharmacopeia BUD recommendations, with this study showing less than 10% degradation over 10 days of refrigerated storage. [ABSTRACT FROM AUTHOR]