Chebychev Trajectory Optimization Program /CHEBYTOP/ Final report

Digital computer program for interplanetary trajectory optimization and variable thrust dat

Who is responsible in winter? Traffic accidents, the fight against hazardous weather and the role of law in a history of risks

This paper analyses the role of law in modern risk debates. Inspired by concepts of historical anthropology, it proposes to put more effort into the historical analysis of law and legal debates in order to understand long-term change in the history of everyday life. The paper takes the discussions on the establishment of a winter service in Germany in the first decades of the twentieth century as an example for this, and demonstrates how legal experts reflected changed perceptions of both nature and related everyday risks and gave them a practical legal meaning by integrating them into existing and widely accepted legal concepts. By doing so, the legal discourse on hazardous weather conditions added significantly to the paradigm shift towards a greater role of the state in the mitigation of everyday risks. As in other debates on everyday risks, law functioned as a hinge between risk perception and risk management

Atomic resolution structure of EhpR: phenazine resistance in Enterobacter agglomerans Eh1087 follows principles of bleomycin / mitomycin C resistance in other bacteria

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background The phenazines are redox-active secondary metabolites that a large number of bacterial strains produce and excrete into the environment. They possess antibiotic activity owing to the fact that they can reduce molecular oxygen to toxic reactive oxygen species. In order to take advantage of this activity, phenazine producers need to protect themselves against phenazine toxicity. Whereas it is believed that phenazine-producing pseudomonads possess highly active superoxide dismutases and catalases, it has recently been found that the plant-colonizing bacterium Enterobacter agglomerans expresses a small gene ehpR to render itself resistant towards D-alanyl-griseoluteic acid, the phenazine antibiotic produced by this strain. Results To understand the resistance mechanism installed by EhpR we have determined its crystal structure in the apo form at 2.15 Å resolution and in complex with griseoluteic acid at 1.01 Å, respectively. While EhpR shares a common fold with glyoxalase-I/bleomycin resistance proteins, the ligand binding site does not contain residues that some related proteins employ to chemically alter their substrates. Binding of the antibiotic is mediated by π-stacking interactions of the aromatic moiety with the side chains of aromatic amino acids and by a few polar interactions. The dissociation constant KD between EhpR and griseoluteic acid was quantified as 244 ± 45 μM by microscale thermophoresis measurements. Conclusions The data accumulated here suggest that EhpR confers resistance by binding D-alanyl-griseoluteic acid and acting as a chaperone involved in exporting the antibiotic rather than by altering it chemically. It is tempting to speculate that EhpR acts in concert with EhpJ, a transport protein of the major facilitator superfamily that is also encoded in the phenazine biosynthesis operon of E. agglomerans. The low affinity of EhpR for griseoluteic acid may be required for its physiological function.Peer Reviewe

Risk as a category of analysis for a social history of the twentieth century: an introduction

Risks are of particular relevance for the social history of the twentieth century. On the one hand, Western societies’ economic growth gave impetus to the rise of new technologies. Technology, we argue, brought with it new possibilities, but it was also loaded with new risks. On the other hand, societies discussed and explored new notions of responsibility for risks, their management and mitigation. Both aspects changed the meaning and perception of traditional risks, such as natural catastrophes, sickness or falling into poverty. In this introduction, we explore the use of risk as a category of analysis for a social history of the twentieth century. In a form of double-intervention on time and methodology, we, on the one hand, hold risks as a 'phenomenon' to be of particular relevance - even characteristic for - the twentieth century; on the other hand, we posit that risk as an analytical category offers us new avenues into understanding modern societies in three important ways: (1) the importance of time and future in human actions and debates, (2) the dual nature of risks as discursively constructed and simultaneously material, (3) the social justice implications of this dual nature that were often unequally shared, be it nationally or globally. In the end, we argue, by linking the materiality of challenges and risks with how these were perceived and discursively constructed, we are better able to understand the rules and the changes that underpin historical societies and which are - as our authors show in this HSR Special Issue - very often determined in reaction to risks

Risk as a category of analysis for a social history of the twentieth century: an introduction

Risks are of particular relevance for the social history of the twentieth century. On the one hand, Western societies’ economic growth gave impetus to the rise of new technologies. Technology, we argue, brought with it new possibilities, but it was also loaded with new risks. On the other hand, societies discussed and explored new notions of responsibility for risks, their management and mitigation. Both aspects changed the meaning and perception of traditional risks, such as natural catastrophes, sickness or falling into poverty. In this introduction, we explore the use of risk as a category of analysis for a social history of the twentieth century. In a form of double-intervention on time and methodology, we, on the one hand, hold risks as a 'phenomenon' to be of particular relevance - even characteristic for - the twentieth century; on the other hand, we posit that risk as an analytical category offers us new avenues into understanding modern societies in three important ways: (1) the importance of time and future in human actions and debates, (2) the dual nature of risks as discursively constructed and simultaneously material, (3) the social justice implications of this dual nature that were often unequally shared, be it nationally or globally. In the end, we argue, by linking the materiality of challenges and risks with how these were perceived and discursively constructed, we are better able to understand the rules and the changes that underpin historical societies and which are - as our authors show in this HSR Special Issue - very often determined in reaction to risks..

Hannah Arendt's Ghosts:Reflections on the Disputable Path from Windhoek to Auschwitz

Historians on both sides of the Atlantic are currently engaged in a controversy about the allegedly genocidal nature of western colonialism and its connections with the mass violence unleashed by Nazi Germany between 1939 and 1945. The debate touches upon some of the most “sensitive” issues of twentieth-century history: the violent “dark side” of modern western civilization, the impact of colonial massacres on the European societies that generated this violence and, perhaps most controversially, the origins and uniqueness of the Holocaust

Caseins as Regulators of Hematopoiesis

The main physiological role of casein, the main protein component in the milk, is to be a source of amino acids that are required for the growth of the neonate; therefore, casein is considered a highly nutritious protein. Over time, it has been revealed that casein is a protein whose physiological importance reaches levels far superior to the food field, having a wide array of biological activities including antimicrobial activities, facilitating absorption of nutrients, as well as acting as a growth factor and an immune stimulant. Here we analyze how caseins can exert numerous hematopoietic and immunomodulatory actions, their role in granulopoiesis, monocytopoiesis, and lymphopoiesis from the early stages of postnatal development seemingly throughout life, and we wonder if casein could be useful to fight pathogens resistant to antibiotics, inducing a strong immune response in immunosuppressed patients, or even be a prophylactic strategy to prevent infections

Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma

Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients

Diversity and plasticity in Rab GTPase nucleotide release mechanism has consequences for Rab activation and inactivation

Ras superfamily GTPase activation and inactivation occur by canonical nucleotide exchange and GTP hydrolysis mechanisms. Despite conservation of active-site residues, the Ras-related Rab GTPase activation pathway differs from Ras and between different Rabs. Analysis of DENND1-Rab35, Rabex-Rab5, TRAPP-Rab1 and DrrA-Rab1 suggests Rabs have the potential for activation by distinct GDP-release pathways. Conserved active-site residues in the Rab switch II region stabilising the nucleotide-free form differentiate these pathways. For DENND1-Rab35 and DrrA-Rab1 the Rab active-site glutamine, often mutated to create constitutively active forms, is involved in GEF mediated GDP-release. By contrast, in Rab5 the switch II aspartate is required for Rabex mediated GDP-release. Furthermore, Rab1 switch II glutamine mutants refractory to activation by DrrA can be activated by TRAPP, showing that a single Rab can be activated by more than one mechanistically distinct GDP-release pathway. These findings highlight plasticity in the activation mechanisms of closely related Rab GTPases.</jats:p