The structure of the substrate-free form of MurB, an essential enzyme for the synthesis of bacterial cell walls

AbstractBackground: The repeating disaccharide and pentapeptide units of the bacterial peptidoglycan layer are connected by a lactyl ether bridge biosynthesized from UDP-N-acetylglucosamine and phosphoenolpyruvate in sequential enol ether transfer and reduction steps catalyzed by MurA and MurB respectively. Knowledge of the structure and mechanism of the MurB enzyme will permit analysis of this unusual enol ether reduction reaction and may facilitate the design of inhibitors as candidate next-generation antimicrobial agents.Results The crystal structure of UDP-N-acetylenolpyruvylglucosamine reductase, MurB, has been solved at 3.0 å and compared with our previously reported structure of MurB complexed with its substrate enolpyruvyl-UDP-N-acetylglucosamine. Comparison of the liganded structure of MurB with this unliganded form reveals that the binding of substrate induces a substantial movement of domain 3 (residues 219–319) of the enzyme and a significant rearrangement of a loop within this domain. These ligand induced changes disrupt a stacking interaction between two tyrosines (Tyr190 and Tyr254) which lie at the side of the channel leading to the active site of the free enzyme.Conclusion The conformational change induced by enolpyruvyl-UDP-N-acetylglucosamine binding to MurB results in the closure of the substrate-binding channel over the substrate. Tyr190 swings over the channel opening and establishes a hydrogen bond with an oxygen of the α-phosphate of the sugar nucleotide substrate which is critical to substrate binding

Dealing with Danger in the CNS: The Response of the Immune System to Injury

Fighting pathogens and maintaining tissue homeostasis are prerequisites for survival. Both of these functions are upheld by the immune system, though the latter is often overlooked in the context of the CNS. The mere presence of immune cells in the CNS was long considered a hallmark of pathology, but this view has been recently challenged by studies demonstrating that immunological signaling can confer pivotal neuroprotective effects on the injured CNS. In this review, we describe the temporal sequence of immunological events that follow CNS injury. Beginning with immediate changes at the injury site, including death of neural cells and release of damage-associated molecular patterns (DAMPs), and progressing through innate and adaptive immune responses, we describe the cascade of inflammatory mediators and the implications of their post-injury effects. We conclude by proposing a revised interpretation of immune privilege in the brain, which takes beneficial neuro-immune communications into account

Robot narratives

There is evidence that humans understand how the world goes through narrative. We discuss what it might mean for embodied robots to understand the world, and communicate that understanding, in a similar manner. We suggest an architecture for adding narrative to robot cognition, and an experimental scenario for investigating the narrative hypothesis in a combination of physical and simulated robots

On Visible Homelessness and the Micro-Aesthetics of Public Space

In this article, we investigate the circumstances that have produced the current municipal regulatory approach to homelessness in the City of Melbourne, Victoria, and the ways in which visibly homeless people are policed through a micro-aesthetics of their presence in public space, which involves the monitoring of their bodily demeanour and their physical possessions. Our study contributes to and draws from a range of debates, including studies of the governmental conjunction of poverty and crime, analysis of the co-implication of law and spatiality, research on the criminalisation of homelessness and homeless people, and the burgeoning criminological interest in the significance of the visual field for our understandings of crime and criminality. This article recounts how homelessness, public space and questions of aesthetics have recently coalesced in debates about the regulation of homelessness in the public space of Melbourne’s city centre. It approaches the issues through comparative consideration of genres of municipal management frameworks in other jurisdictions, detailed textual consideration of the Protocol on Homelessness in the City of Melbourne and an empirical study of visible homelessness in the public places of central Melbourne

Budget Perspectives 2013. RESEARCH SERIES NUMBER 28 September 2012

The annual Budget Perspectives Conference provides a forum for discussing key public policy issues of both immediate and longer term concern. In the context of the current fiscal and economic crisis, research insights are needed at both the macro and micro level. The former are central to understanding and managing the significant reductions in the budget deficit needed to put Ireland's public finances on a sustainable footing. The latter are essential because a successful budgetary adjustment requires restructuring of both public expenditure and taxation. This in turn requires that policy adjustments take full account of both efficiency and equity issue and are seen to do so. The research papers presented at this year's annual Budget Perspectives Conference continue in this tradition, providing an opportunity for policymakers, social partners and researchers to engage with some of the major current issues

Enzymatic Glycosylation of Vancomycin Aglycon: Completion of a Total Synthesis of Vancomycin and N- and C-Terminus Substituent Effects of the Aglycon Substrate

Studies on the further development of the sequential glycosylations of the vancomycin aglycon catalyzed by the glycosyltransferases GtfE and GtfD and the observation of unusual, perhaps unexpected, aglycon substrate substituent effects on the rate and efficiency of the initial glycosylation reaction are reported

Catheter ablation of accessory atrioventricular pathways in young patients: Use of long vascular sheaths, the transseptal approach and a retrograde left posterior parallel approach

AbstractObjectives. This study retrospectively assesses the technical aspects of the catheter techniques used to ablate 83 accessory atrioventricular (AV) pathways during 88 procedures in 71 pediatric and adult patients (median age 14 years, range 1 month to 55 years). A number of catheter approaches and techniques evolved that may have improved success and shortened procedure times.Background. Radiofrequency catheter ablation of accessory AV pathways can be highly successful. However, the technical difficulty of many of the procedures is masked by the success rate.Methods. Left free wall, right free wall and septal accessory pathways were ablated with a variety of approaches.Results. Left free wall pathways were ablated successfully by using a standard retrograde approach through the aortic valve in only 10 (24%) of 43 cases. The remaining 33 (76%) required an approach that was either retrograde through the mitral valve (2 of 33), transseptal (21 of 33) or retrograde where the catheter was advanced behind the posterior mitral leaflet at the point of mitral-aortic continuity, so that the catheter course was parallelrather than perpendicularto the mitral anulus (10 of 33). Nineteen of 20 septal pathways were ablated successfully by using either the parallel approach (2 of 29), a transseptal approach (2 of 19), ablation within the coronary sinus or one of its veins (8 of 19) or ablation on the atrial side of the tricuspid valve (7 of 19). Fifteen of 20 right free wall pathways were ablated successfully with a variety of approaches on both the atrial and the ventricular side of the tricuspid valve. Long vascular sheaths were judged to contribute directly to success in 33 (43%) of 77 pathways. The overall success rate has been 93% (77 of 83 pathways), with 100% success for left free wall (43 of 43), 75% for right free wall (15 of 20) and 95% for septal pathways (19 of 20).Conclusions. Thus, successful ablation of accessory AV pathways in a mixed group of pediatric and adult patients appears to benefit from a wide range of vascular and catheter approaches

Sexual violation of patients by physicians: A mixed-methods, exploratory analysis of 101 cases

A mixed-method, exploratory design was used to examine 101 cases of sexual violations in medicine. The study involved content analysis of cases to characterize the physicians, patient-victims, the practice setting, kinds of sexual violations, and consequences to the perpetrator. In each case, a criminal law framework was used to examine how motives, means, and opportunity combined to generate sexual misconduct. Finally, cross-case analysis was performed to identify clusters of causal factors that explain specific kinds of sexual misconduct. Most cases involved a combination of five factors: male physicians (100%), older than the age of 39 (92%), who were not board certified (70%), practicing in nonacademic settings (94%) where they always examined patients alone (85%). Only three factors (suspected antisocial personality, physician board certification, and vulnerable patients) differed significantly across the different kinds of sexual abuse: personality disorders were suspected most frequently in cases of rape, physicians were more frequently board certified in cases of consensual sex with patients, and patients were more commonly vulnerable in cases of child molestation. Drawing on study findings and past research, we offer a series of recommendations to medical schools, medical boards, chaperones, patients, and the national practitioners database