The organophosphate-degrading enzyme from Agrobacterium radiobacter displays mechanistic flexibility for catalysis

The OP (organophosphate)-degrading enzyme from Agrobacterium radiobacter (OpdA) is a binuclear metallohydrolase able to degrade highly toxic OP pesticides and nerve agents into less or non-toxic compounds. In the present study, the effect of metal ion substitutions and site-directed mutations on the catalytic properties of OpdA are investigated. The study shows the importance of both the metal ion composition and a hydrogenbond network that connects the metal ion centre with the substrate-binding pocket using residues Arg254 and Tyr257 in the mechanism and substrate specificity of this enzyme. For theCo(II) derivative of OpdA two protonation equilibria (pKa1 ∼5; pKa2 ∼10) have been identified as relevant for catalysis, and a terminal hydroxide acts as the likely hydrolysis-initiating nucleophile. In contrast, the Zn(II) and Cd(II) derivatives only have one relevant protonation equilibrium (pKa ∼4–5), and theμOHis the proposed nucleophile. The observed mechanistic flexibility may reconcile contrasting reaction models that have been published previously and may be beneficial for the rapid adaptation of OP-degrading enzymes to changing environmental pressures

The Stellenbosch Consensus on the International Legal Obligation to Collaborate and Assist in Addressing Pandemics: Clarifying Article 44 of the International Health Regulations

The International Health Regulations (IHR), of which the World Health Organization is custodian, govern how countries collectively promote global health security, including prevention, detection, and response to potential global health emergencies such as the ongoing covid-19 pandemic. While Article 44 of this binding legal instrument requires countries to collaborate and assist each other in meeting their respective obligations, recent events demonstrate that the precise nature and scope of these legal obligations are ill-understood. A shared understanding of the level and type of collaboration legally required by the IHR is a necessary step in ensuring these obligations can be acted upon and fully realized, and in fostering global solidarity and resilience in the face of future pandemics. In this consensus statement, public international law scholars specializing in global health consider the legal meaning of Article 44 using the interpretive framework of the Vienna Convention on the Law of Treaties

Asymmetric zinc(II) complexes as functional and structural models for phosphoesterases

We report two asymmetric ligands for the generation of structural and functional dinuclear metal complexes as phosphoesterase mimics. Two zinc(II) complexes, [Zn-2(CH(3)L4)(CH3CO2)(2)](+) (CH(3)HL4 = 2-(((2methoxyethyl)(pyridin-2-ylmethyl) amino) methyl)-4-methyl-6-(((pyridin-2-ylmethyl) amino) methyl)phenol) and [Zn-2(CH(3)L5)(CH3CO2)(2)](+) (CH(3)HL5 = 2-(((2-methoxyethyl)(pyridine-2-ylmethyl) amino)methyl)- 4-methyl-6-(((pyridin-2-ylmethyl)(4-vinylbenzyl) amino) methyl) phenol) were synthesized and characterized by X-ray crystallography. The structures showed that the ligands enforce a mixed 6,5-coordinate environment in the solid state. H-1-, C-13-and P-31-NMR, mass spectrometry and infrared spectroscopy were used to further characterize the compounds in the solid state and in solution. The zinc(II) complexes hydrolyzed the organophosphate substrate bis-(2,4-dinitrophenol) phosphate (BDNPP), the nucleophile proposed to be a terminal water molecule (pK(a) 7.2). The ligand CH3HL4 was immobilised on Merrifield resin and its zinc(II) complex generated. Infrared spectroscopy, microanalysis and XPS measurements confirmed successful immobilisation, with a catalyst loading of similar to 1.45 mmol g(-1) resin. The resin bound complex was active towards BDNPP and displayed similar pH dependence to the complex in solution

“Excellence R Us”: university research and the fetishisation of excellence

The rhetoric of “excellence” is pervasive across the academy. It is used to refer to research outputs as well as researchers, theory and education, individuals and organisations, from art history to zoology. But does “excellence” actually mean anything? Does this pervasive narrative of “excellence” do any good? Drawing on a range of sources we interrogate “excellence” as a concept and find that it has no intrinsic meaning in academia. Rather it functions as a linguistic interchange mechanism. To investigate whether this linguistic function is useful we examine how the rhetoric of excellence combines with narratives of scarcity and competition to show that the hypercompetition that arises from the performance of “excellence” is completely at odds with the qualities of good research. We trace the roots of issues in reproducibility, fraud, and homophily to this rhetoric. But we also show that this rhetoric is an internal, and not primarily an external, imposition. We conclude by proposing an alternative rhetoric based on soundness and capacity-building. In the final analysis, it turns out that that “excellence” is not excellent. Used in its current unqualified form it is a pernicious and dangerous rhetoric that undermines the very foundations of good research and scholarship

A dual-process approach to exploring the role of delay discounting in obesity

Delay discounting of financial rewards has been related to overeating and obesity. Neuropsychological evidence supports a dual-system account of both discounting and overeating behaviour where the degree of impulsive decision making is determined by the relative strength of reward desire and executive control. A dual-parameter model of discounting behaviour is consistent with this theory. In this study, the fit of the commonly used one-parameter model was compared to a new dual-parameter model for the first time in a sample of adults with wide ranging BMI. Delay discounting data from 79 males and females (Males=26) across a wide age (M=28.44 years (SD=8.81)) and BMI range (M=25.42 (SD=5.16)) was analysed. A dual-parameter model (saturating-hyperbolic; Doya, 2008) was applied to the data and compared on model fit indices to the single-parameter model. Discounting was significantly greater in the overweight/obese participants using both models, however, the two parameter model showed a superior fit to data (p<.0001). The two parameters were shown to be related yet distinct measures consistent with a dual-system account of inter-temporal choice behaviour.The dual-parameter model showed superior fit to data and the two parameters were shown to be related yet distinct indices sensitive to differences between weight groups. Findings are discussed in terms of the impulsive reward and executive control systems that contribute to unhealthy food choice and within the context of obesity related research

The role of Zn-OR and Zn-OH nucleophiles and the influence of para-substituents in the reactions of binuclear phosphatase mimetics

Analogues of the ligand 2,2'-(2-hydroxy-5-methyl-1,3-phenylene)bis(methylene)bis((pyridin-2-ylmethyl)azanediyl)diethanol (CH(3)H(3)L1) are described. Complexation of these analogues, 2,6-bis(((2-methoxyethyl)(pyridin-2-ylmethyl)amino)methyl)-4-methylphenol (CH(3)HL2), 4-bromo-2,6-bis(((2-methoxyethyl)(pyridin-2-ylmethyl)amino)methyl)phenol (BrHL2), 2,6-bis(((2-methoxyethyl)(pyridin-2-ylmethyl)amino)methyl)-4-nitrophenol (NO(2)HL2) and 4-methyl-2,6-bis(((2-phenoxyethyl)(pyridin-2-ylmethyl)amino)methyl)phenol (CH(3)HL3) with zinc(II) acetate afforded [Zn-2(CH(3)L2)(CH3COO)(2)](PF6), [Zn-2(NO(2)L2)(CH3COO)(2)](PF6), [Zn-2(BrL2)(CH3COO)(2)](PF6) and [Zn-2(CH(3)L3)(CH3COO)(2)](PF6), in addition to [Zn-4(CH(3)L2)(2)(NO2C6H5OPO3)(2)(H2O)(2)](PF6)(2) and [Zn-4(BrL2)(2)(PO3F)(2)(H2O)(2)](PF6)(2). The complexes were characterized using H-1 and C-13 NMR spectroscopy, mass spectrometry, microanalysis, and X-ray crystallography. The complexes contain either a coordinated methyl-(L2 ligands) or phenyl-(L3 ligand) ether, replacing the potentially nucleophilic coordinated alcohol in the previously reported complex [Zn-2(CH(3)HL1)(CH3COO)(H2O)](PF6). Functional studies of the zinc complexes with the substrate bis(2,4-dinitrophenyl) phosphate (BDNPP) showed them to be competent catalysts with, for example, [Zn-2(CH(3)L2)](+), k(cat) = 5.70 +/- 0.04 x 10(-3) s(-1) (K-m = 20.8 +/- 5.0 mM) and [Zn-2(CH(3)L3)](+), kcat = 3.60 +/- 0.04 x 10(-3) s(-1) (K-m = 18.9 +/- 3.5 mM). Catalytically relevant pK(a)s of 6.7 and 7.7 were observed for the zinc(II) complexes of CH(3)L2(-) and CH(3)L3(-), respectively. Electron donating para-substituents enhance the rate of hydrolysis of BDNPP such that k(cat) p-CH3 > p-Br > p-NO2. Use of a solvent mixture containing H2O18/H2O16 in the reaction with BDNPP showed that for [Zn-2(CH(3)L2)(CH3COO)(2)](PF6) and [Zn-2(NO(2)L2)(CH3COO)(2)](PF6), as well as [Zn-2(CH(3)HL1)(CH3COO)(H2O)](PF6), the O-18 label was incorporated in the product of the hydrolysis suggesting that the nucleophile involved in the hydrolysis reaction was a Zn-OH moiety. The results are discussed with respect to the potential nucleophilic species (coordinated deprotonated alcohol versus coordinated hydroxide)

Developing Practice-Oriented Theory on Collaboration: A Paradox Lens

Collaboration is present throughout public administration as a means to address social issues that sit in the inter-organizational domain. Yet research carried out over the last three decades concludes that collaborations are complex, slow to produce outputs, and by no means guaranteed to deliver synergies and advantage. For these reasons, this article explores whether a ‘paradox lens’ can aid the development of practice-oriented theory to help those who govern, lead and manage collaboration in practice. It draws on a long standing research program on collaboration and a synthesis of literature on paradox of relevance to collaboration. The article develops five propositions on the application of a paradox lens that explicitly recognizes the context of collaboration as inherently paradoxical; acknowledges the limitation of mainstream theory in capturing adequately the complex nature of and tensions embedded in collaborative contexts and uses the principles of paradox to develop practice-oriented theory on governing, leading and managing collaborations

Travel restrictions and variants of concern: global health laws need to reflect evidence

As the coronavirus disease 2019 (COVID-19) spread in the early days of the pandemic, governments neglected World Health Organization (WHO) guidance and imposed travel restrictions. These public health measures employed varied levels of restrictiveness at national borders, in some cases banning all travel between countries. Where these border control measures were undertaken for domestic political reasons, enacted without consideration of public health evidence, they divided the world when solidarity was needed most.1 Such measures undermined global health law that countries have established as a foundation for preventing and responding to public health emergencies of international concern. With the emergence of the Omicron variant, national governments once again returned to international travel restrictions, posing challenges for the rule of law in global health governance. Future reforms of global health law must account for this continuing impulse to enact travel restrictions, ensuring that international legal obligations reflect evolving public health evidence

The Stellenbosch Consensus on legal national responses to public health risks : clarifying Article 43 of the International Health Regulations

The International Health Regulations (ihr), of which the World Health Organization is custodian, govern how countries collectively promote global health security, including prevention, detection, and response to global health emergencies such as the ongoing covid-19 pandemic. Countries are permitted to exercise their sovereignty in taking additional health measures to respond to such emergencies if these measures adhere to Article 43 of this legally binding instrument. Overbroad measures taken during recent public health emergencies of international concern, however, reveal that the provision remains inadequately understood. A shared understanding of the measures legally permitted by Article 43 is a necessary step in ensuring the fulfillment of obligations, and fostering global solidarity and resilience in the face of future pandemics. In this consensus statement, public international law scholars specializing in global health consider the legal meaning of Article 43 using the interpretive framework of the Vienna Convention on the Law of Treaties

Infrared target and background radiometric measurements--concepts units and techniques

This report discusses concepts units and techniques for making and describing measurements of radiation from targets and backgrounds.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32197/1/0000256.pd