Dynamins are mechano-chemical GTPases involved in the remodeling of cellular membranes. In this study, we have investigated the mechanism of dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission. To date, it is unclear how Drp1 assembles on the mitochondrial outer membrane in response to different lipid signals to induce membrane fission. Here, we present cryo-EM structures of Drp1 helices on nanotubes with distinct lipid compositions to mimic membrane interactions with the fission machinery. These Drp1 polymers assemble exclusively through stalk and G-domain dimerizations, which generates an expanded helical symmetry when compared to other dynamins. Interestingly, we found the characteristic gap between Drp1 and the lipid bilayer was lost when the mitochondrial specific lipid cardiolipin was present, as Drp1 directly interacted with the membrane. Moreover, this interaction leads to a change in the helical structure, which alters G-domain interactions to enhance GTPase activity. These results demonstrate how lipid cues at the mitochondrial outer membrane (MOM) can alter Drp1 structure to activate the fission machinery.
Many countries have attempted to transition to democracy following conflict or repression, but the basic meaning of transitional justice remains hotly contested. In this book, Colleen Murphy analyzes transitional justiceshowing how it is distinguished from retributive, corrective, and distributive justiceand outlines the ethical standards that societies attempting to democratize should follow. She argues that transitional justice involves the just pursuit of societal transformation. Such transformation requires political reconciliation, which in turn has a complex set of institutional and interpersonal requirements, including the rule of law. She shows how societal transformation is also influenced by the moral claims of victims and the demands of perpetrators, and how justice processes can fail to be just by failing to foster this transformation or by not treating victims and perpetrators fairly. Her book will be accessible and enlightening for philosophers, political and social scientists, policy analysts, and legal and human rights scholars and activists.
p38 MAP kinase-induced TNF alpha production plays a central role in the development of pulmonary dysfunction, which accompanies severe acute pancreatitis in this rodent model.
Policy and Management-Values, technology and innovation, delft university of technology, delft, the netherlands; b department of civil and environmental engineering, university of illinois at urbana-champaign, urbana, il, uSa; c college of law, university of illinois at urbana-champaign, champaign, il, uSa
In this paper, we present a Capabilities-based Approach to the acceptability and the tolerability of risks posed by natural and man-made hazards. We argue that judgments about the acceptability and/or tolerability of such risks should be based on an evaluation of the likely societal impact of potential hazards, defined in terms of the expected changes in the capabilities of individuals. Capabilities refer to the functionings, or valuable doings and beings, individuals are able to achieve given available personal, material, and social resources. The likely impact of a hazard on individuals' capabilities should, we argue, be compared against two separate thresholds. The first threshold specifies the minimum level of capabilities attainment that is acceptable in principle for individuals to have in the aftermath of a hazard over any period of time. This threshold captures the level that individuals' capabilities ideally should not fall below. A risk is acceptable if the probability that the attained capabilities will be less than the acceptable level is sufficiently small. In practice, it can be tolerable for some individuals to temporarily fall below the acceptable threshold, provided this situation of lower capabilities attainment is temporary, reversible, and the probability that capabilities will fall below a tolerability threshold is sufficiently small. This second, tolerable threshold delimits an absolute minimum level of capabilities attainment below which no individual in a society should ever fall, regardless of whether that level of capabilities attainment is temporary or reversible. In this paper, we describe and justify this Capabilities-based Approach to the acceptability and tolerability of risks. We argue that the proposed theoretical framework avoids the limitations in current approaches to acceptable risk. The proposed approach focuses the attention of risk analysts directly on what should be our primary concern when judging the acceptability and the tolerability of risks, namely, how risks impact the well-being of individuals in a society. Also, our Capabilities-based Approach offers a transparent, easily communicable way for determining the acceptability and the tolerability of risks.
Antimicrobial resistance is a complex issue with a large volume of published literature, and there is a need for synthesis of primary studies for an integrated understanding of this topic. Our research team aimed to have a more complete understanding of antimicrobial resistance in Canada (IAM.AMR Project) using multiple methods including the literature reviews and quantitative modelling. To accomplish this goal, qualitative features of publications (e.g., geographical location, study population) describing potential relationships between the occurrence of antimicrobial resistance and factors (e.g., antimicrobial use; management system) were of particular interest. The objectives of this review were to (a) describe the available peer-reviewed literature reporting potential relationships between factors and antimicrobial resistance; and (b) to highlight data gaps. A comprehensive literature search and screening were performed to identify studies investigating factors potentially linked with antimicrobial resistance in Campylobacter species, Escherichia coli and Salmonella enterica along the farm-to-fork pathway (farm, abattoir (slaughter houses) and retail meats) for the major Canadian livestock species (beef cattle, broiler chicken and pigs). The literature search returned 14,966 potentially relevant titles and abstracts. Following screening of titles, abstracts and full-text articles, the qualitative features of retained studies (n = 28) were extracted. The most common factors identified were antimicrobial use (n = 13 studies) and type of farm management system (e.g., antibiotic-free, organic; n = 8). Most studies were conducted outside of Canada and involved investigations at the farm level. Identified data gaps included the effect of vaccination, industry-specific factors (e.g., livestock density) and factors at sites other than farm along the agri-food chain. Further investigation of these factors and other relevant industry activities are needed for the development of quantitative models that aim to identify effective interventions to mitigate the occurrence of antimicrobial resistance along the agri-food chain.
This article proposes a new conceptual framework in engineering risk analysis to account for the net impact of hazards on individuals in a society. It analyzes four limitations of prevailing approaches to risk analysis and suggests a way to overcome them. These limitations are a result of how societal impacts are characteristically accounted for and valued. Prevailing approaches typically focus too narrowly on the consequences of natural or man-made hazards, not accounting for the broader societal impacts of such hazards. Such approaches lack a uniform and consistent metric for accounting for the impact of the nonquantifiable consequences (like psychological trauma or societal impacts) and rely upon implicit and potentially inaccurate value judgments when evaluating risks. To overcome these limitations, we propose an alternative, Capabilities-Based Approach to the treatment of society in risk analysis. A similar approach is currently used by the United Nations to quantitatively measure the degree of development in countries around the world. In a Capabilities-Based Approach, the potential benefits and losses due to a hazard are measured and compared in a uniform way by using individual capabilities (functionings individuals are able, still able, or unable to achieve) as a metric. This Capabilities-Based Approach provides a foundation for identifying and quantifying the broader, complex societal consequences of hazards and is based on explicit, value judgments. The Capabilities-Based Approach can accommodate different methods or techniques for risk determination and for risk evaluation and can be used in assessing risk in diverse types of hazards (natural or man-made) and different magnitudes that range from minor to catastrophic. In addition, implementing a Capabilities-Based Approach contributes to the development of a single standard for public policy decision making, since a Capabilities-Based Approach is already in use in development economics and policy.
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