The denatured state of N-PGK is compact and predominantly disordered

The Organisation of the structure present in the chemically denatured N-terminal domain of phosphoglycerate kinase (N-PGK) has been determined by paramagnetic relaxation enhancements (PREs) to define the conformational landscape accessible to the domain. Below 2.0 M guanidine hydrochloride (GuHCl), a species of N-PGK (denoted I-b) is detected, distinct from those previously characterised by kinetic experiments [folded (F), kinetic intermediate (I-k) and denatured (D)]. The transition to I-b is never completed at equilibrium, because F predominates below 1.0 M GuHCl. Therefore, the ability of PREs to report on transient or low population species has been exploited to characterise I-b. Five single cysteine variants of N-PGK were labelled with the nitroxide electron spin-label MTSL [(1-oxyl-2,2,5,5-tetramethyl-3-pyrroline-3-methyl)methanesulfonate] and the denaturant dependences of the relaxation properties of the amide NMR signals between 1.2 and 3.6 M GuHCl were determined. Significant PREs for I-b were obtained, but these were distributed almost uniformly throughout the sequence. Furthermore, the PREs indicate that no specific short tertiary contacts persist. The data indicate a collapsed state with no coherent three-dimensional structure, but with a restricted radius beyond which the protein chain rarely reaches. The NMR characteristics Of I-b indicate that it forms from the fully denatured state within 100 mu s, and therefore a rapid collapse is the initial stage of folding of N-PGK from its chemically denatured state. By extrapolation, I-b is the predominant form of the denatured state under native conditions, and the non-specifically collapsed structure implies that many non-native contacts and chain reversals form early in protein folding and must be broken prior to attaining the native state topology. (C) 2008 Elsevier Ltd. All rights reserved

An International Review of Disciplinary Measures in Geoscience—Both Procedures and Actions

As professional communities around the world, geoscientists have in place disciplinary measures and, over time, instances have occurred which have required disciplinary actions to be taken against individuals. Geoscientists have specialized knowledge and provide expertise on which others rely for important decision- making. Geoscientists are best positioned to judge the scientific/technical and ethical merits of the work of other geoscientists. They are considered professionals and for that reason, society has placed the onus on the profession to govern itself. Consequently, it is important that appropriate disciplinary procedures are in place, that they are ever improving, and that the profession can and does act decisively when necessary.    This two-part review paper examines systems and measures to uphold the ethical conduct of geoscientists (Part 1), and studies actions taken against geoscientists in the last three decades (Part 2). It uses available information collected from the member organizations of the International Union of Geological Sciences’ Task Group on Global Geoscience Professionalism as well as public sources.    Models used for the governance and self-regulation of geoscience practice vary globally across the same spectrum that is typical in other professions, with the choice of model varying to suit local legal contexts and societal needs and norms. Broadly, similar processes for complaints, investigation, and disciplinary decision-making (and appeals of decisions) are used. The types of charges that can be made for offences or allegations are similar. The ranges of applicable penalties vary depending on the extent of statutory power in place, but beyond this constraint, there are many parallels.    Ninety-two documented cases are identified where action has been taken against geoscientists globally since 1989. Of these, 40 relate to either non-payment of dues or fees (usually discontinuation of a membership or license) or to non-compliance with Continuing Professional Development requirements. The remaining 52 are actions for more serious offenses, resulting in penalties that are more substantial. These offences cluster into six categories: 1) falsifying data; 2) fraudulent billing and/or falsifying time sheets; 3) inappropriate behaviour towards others; 4) problematic geoscience work and/or technical deficiencies; 5) misrepresentation of findings, or the giving of unsupported opinions; and 6) mixed other offences. The most frequently used penalty in these cases is the reprimand. Next most frequent is revocation. Revocations include resignations with prejudice, where the geoscientist chose to resign their membership rather than allow the matter to proceed to discipline. Suspensions, requirements for remedial education and/or fines are also frequent penalties. Combinations of different penalties are common.    It is evident that rigorous procedures are in place in a number of countries and that they are being used to address the unprofessional behaviour of geoscientists. Transparency and the sharing of information about disciplinary actions between geoscience professional organizations (of all types) is important and should be encouraged. A global repository of geoscience disciplinary actions should be established and kept as up to date as possible.RÉSUMÉÀ l’instar des autres organismes professionnels à travers le monde, les géoscientifiques possèdent leur protocole de mesures disciplinaires. Il est arrivé à quelques reprises que ces mesures aient été mises en application et que des sanctions disciplinaires aient été intentées contre certains individus. Un géoscientifique possède une connaissance spécialisée et livre une expertise qui, en retour, peut servir de référence dans la prise d’importantes décisions. Il n’existe aucun autre professionnel qu’un géoscientifique pour évaluer les mérites d’ordres moral, scientifique et technique d’un de ses pairs. Et c’est en se basant sur le professionnalisme de la géoscience que la société a imputé la responsabilité d’auto-gouvernance à la profession. Par conséquent, il est important que des mesures disciplinaires soient, non seulement mises en place, mais qu’elles soient également régulièrement revisitées. Et il est tout aussi important que la profession puisse agir et prendre ses responsabilités lorsqu’il est jugé nécessaire.   Cette étude qui comporte deux volets traite, en premier lieu, des systèmes et des mesures mis en place pour entériner le code de conduite des géoscientifiques et en deuxième lieu, elle examine les actions intentées à l’encontre des géoscientifiques durant les 30 dernières années. Notre ouvrage est basé sur des données et des renseignements recueillis d’associations membres du Groupe de travail de l’Union Internationale des sciences géologiques sur le Professionnalisme géoscientifique mondial ainsi que de sources publiques.   Comme on peut s’y attendre, les modèles qui sont utilisés pour la gouvernance et l’autoréglementation de l’exercice de la géoscience à travers le monde diffèrent de pays en pays, dépendant des contextes légaux des différentes régions, de leurs besoins particuliers et des coutumes sociales. En gros, les mêmes processus sont utilisés pour les plaintes, les enquêtes et les prises de décisions de sanctions (et les appels des jugements rendus). Les différents types de sanctions qui sont rendues pour les infractions ou allégations sont les mêmes. La nature des mesures punitives applicables demeure tributaire des pouvoirs statutaires en vigueur, mais à part cette contrainte, on a pu dresser entre elles plusieurs parallèles.   Nous avons identifié quatre-vingt-douze cas, documentés, où des actions ont été intentées contre des géoscientifiques à l’échelle mondiale depuis 1989. De ces 92 cas, 40 concernent, soit le défaut de paiement de cotisations ou frais d’adhésion (en général, il s’agit d’une suspension d’adhésion ou de droit d’exercice), soit le manque de conformité aux exigences des programmes de Développement professionnel continu. Les 52 cas qui restent ont trait à des offenses plus sérieuses qui ont donné suite à des sanctions plus graves. Les infractions ont été divisées en six catégories: 1) falsification de données; 2) facturation frauduleuse et/ou falsification des relevés de temps; 3) comportement inapproprié vis-à-vis d’autres personnes; 4) situations de travail géoscientifique problématiques et/ou irrégularités d’ordre technique; 5) fausse déclaration de résultats ou énoncé d’opinions sans preuves; et 6) autres diverses infractions. La mesure punitive la plus répandue pour ce genre d’offenses est la réprimande. Puis, la deuxième plus répandue est la révocation. La révocation peut inclure une démission volontaire sans appel, c’est-à-dire que le géoscientifique choisit de renoncer à son adhésion à la profession plutôt que de voir son cas jugé. D’autres sanctions qui reviennent souvent comportent des suspensions, des amendes et des ordres d’éducation complémentaire. On retrouve également fréquemment des combinaisons de sanctions différentes.   Il est évidentqu’il existe des procédures rigoureuses dans de nombreux pays et que ces procédures sont donc mises en œuvre pour gérer les inconduites professionnelles des géoscientifiques. La transparence et le partage de l’information concernant les mesures disciplinaires entre tous les différents organismes professionnels géoscientifiques sont extrêmement importants et doivent être encouragés. Un répertoire mondial des mesures disciplinaires en géoscience doit être mis sur pied et doit être constamment mis à jour aussi souvent que possible

A genealogical critique of Beauchamp and Childress' for principles approach to medical ethics

Part Three examines the development of Beauchamp and Childress 'four principles' approach to medical ethics from the 1 st to the 6th Editions of Principles of Biomedical Ethics, arguing that it has, thanks to changes in the authors' conception of philosophical moral theory, been able to productively incorporate the views of many of its critics over this time; that it is also able to incorporate features of different ethical approaches such as virtue ethics, narrative ethics and ethics of care; and that, properly understood, it continues to provide a good framework both for moral reflection in medicine and the provision of concrete action-guides. The thesis concludes by considering this view of the four principles in the light of the earlier sections' approach, and attempting to demonstrate further demonstrate their value through two case-studies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Green Supply Chain Network Design with Emission Sensitive Demand

Over the last few decades, the argument for a link between greenhouse gas emissions and global warming has become stronger. In response, there has been a global shift. Politicians are implementing carbon policies while consumers are becoming more aware of their own impact on the environment. This thesis explores how environmental policies and consumer awareness impact supply chain network design and provides a new modelling framework in which demand is dependent on carbon footprint. In the first part of the thesis, a comprehensive literature review on green supply chain network design between 2010 and mid 2017 is presented. The review focuses on models and methodologies that explicitly include carbon emissions and environmental policies. It is evident that incorporating carbon policy is popular, particularly carbon cap, carbon offset, cap-and-trade, and carbon tax. By reconfiguring the supply chain and investing in lower-emitting resources, each policy is able to achieve significant emission reduction with marginal increase in total cost. This is achieved by reconfiguring the supply chain and investing in lower-emitting resources. The review finds that there is a lack of models that consider the complex nature of emissions. Other complexities, such as multivariate emissions and uncertainty, are considered in only a few papers. Most importantly, however, it is clear that demand as a function of supply chain emissions is rarely accounted for in supply chain network design literature. In the second part, a two echelon supply chain with emission sensitive demand is considered. A new model is provided that determines at which points investments in lower emitting technologies at the warehouses is necessary. Being nonlinear due to the complex carbon footprint constraint, the resulting model is first reformulated as a second-order cone program, and is tested on a hypothetical e-commerce supply chain. The results illustrate that without proper response to consumer preferences, companies will lose out on revenue. It also illustrates investments are made at clear points as consumer sensitivity to emissions increases, rather than continuously. This work is important for e-commerce companies who wish to set themselves apart from competitors by catering to environmentally conscious consumers. The third part of the thesis presents a new model for green supply chain network design with emission sensitive demand. The supply chain is composed of one plant and multiple warehouses that serve multiple customer zones. Decisions pertaining to the technology type used at the plant, the location and technology of the warehouses, the assignment of customer zones to warehouses, and the flow between the different echelons are modelled. In addition, demand is modelled as a function of carbon footprint. The resulting model is nonlinear due to the carbon footprint constraint. To be able to solve it, we reformulate the problem as a second-order cone program. To test the model and draw insights from it, we build a hypothetical, but realistic potato chip supply chain located in the province of Ontario, Canada. The testing confirms the ability of the model to trade-off between demand and emissions for environmentally conscious customers and provides insight into to how companies could advertise carbon footprint information to capture demand, and their potential impact on the supply chain

A genealogical critique of Beauchamp and Childress' for principles approach to medical ethics.

Part Three examines the development of Beauchamp and Childress 'four principles' approach to medical ethics from the 1 st to the 6th Editions of Principles of Biomedical Ethics, arguing that it has, thanks to changes in the authors' conception of philosophical moral theory, been able to productively incorporate the views of many of its critics over this time; that it is also able to incorporate features of different ethical approaches such as virtue ethics, narrative ethics and ethics of care; and that, properly understood, it continues to provide a good framework both for moral reflection in medicine and the provision of concrete action-guides. The thesis concludes by considering this view of the four principles in the light of the earlier sections' approach, and attempting to demonstrate further demonstrate their value through two case-studies

The roughness of the protein energy landscape results in anomalous diffusion of the polypeptide backbone

Some of this work was supported by grants from the NIH and BBSRC

(FNMR)-F-19 and DFT Analysis Reveal Structural and Electronic Transition State Features for RhoA-Catalyzed GTP Hydrolysis

Molecular details for RhoA/GAP catalysis of the hydrolysis of GTP to GDP are poorly understood. We use 19F NMR chemical shifts in the MgF3− transition state analogue (TSA) complex as a spectroscopic reporter to indicate electron distribution for the γ-PO3− oxygens in the corresponding TS, implying that oxygen coordinated to Mg has the greatest electron density. This was validated by QM calculations giving a picture of the electronic properties of the transition state (TS) for nucleophilic attack of water on the γ-PO3− group based on the structure of a RhoA/GAP-GDP-MgF3− TSA complex. The TS model displays a network of 20 hydrogen bonds, including the GAP Arg85′ side chain, but neither phosphate torsional strain nor general base catalysis is evident. The nucleophilic water occupies a reactive location different from that in multiple ground state complexes, arising from reorientation of the Gln-63 carboxamide by Arg85′ to preclude direct hydrogen bonding from water to the target γ-PO3− group

How to name atoms in phosphates, polyphosphates, their derivatives and mimics, and transition state analogues for enzyme-catalysed phosphoryl transfer reactions (IUPAC Recommendations 2016)

Procedures are proposed for the naming of individual atoms, P, O, F, N, and S in phosphate esters, amidates, thiophosphates, polyphosphates, their mimics, and analogues of transition states for enzyme-catalyzed phosphoryl transfer reactions. Their purpose is to enable scientists in very different fields, e.g. biochemistry, biophysics, chemistry, computational chemistry, crystallography, and molecular biology, to share standard protocols for the labelling of individual atoms in complex molecules. This will facilitate clear and unambiguous descriptions of structural results, as well as scientific intercommunication concerning them. At the present time, perusal of the Protein Data Bank (PDB) and other sources shows that there is a limited degree of commonality in nomenclature, but a large measure of irregularity in more complex structures. The recommendations described here adhere to established practice as closely as possible, in particular to IUPAC and IUBMB recommendations and to "best practice" in the PDB, especially to its atom labelling of amino acids, and particularly to Cahn-Ingold-Prelog rules for stereochemical nomenclature. They are designed to work in complex enzyme sites for binding phosphates but also to have utility for non-enzymatic systems. Above all, the recommendations are designed to be easy to comprehend and user-friendly

Mapping local structural perturbations in the native state of stefin B (cystatin B) under amyloid forming conditions

Unlike a number of amyloid-forming proteins, stefins, and in particular stefin B (cystatin B) form amyloids under conditions where the native state predominates. In order to trigger oligomerization processes, the stability of the protein needs to be compromised, favoring structural re-arrangement however, accelerating fibril formation is not a simple function of protein stability. We report here on how optimal conditions for amyloid formation lead to the destabilization of dimeric and tetrameric states of the protein in favor of the monomer. Small, highly localized structural changes can be mapped out that allow us to visualize directly areas of the protein which eventually become responsible for triggering amyloid formation. These regions of the protein overlap with the Cu (II)-binding sites which we identify here for the first time. We hypothesize that in vivo modulators of amyloid formation may act similarly to painstakingly optimized solvent conditions developed in vitro. We discuss these data in the light of current structural models of stefin B amyloid fibrils based on H-exchange data, where the detachment of the helical part and the extension of loops were observed