Mechanistic insights into the C₅₅-P targeting lipopeptide antibiotics revealed by structure-activity studies and high-resolution crystal structures

AbstractThe continued rise of antibiotic resistance is a global concern that threatens to undermine many aspects of modern medical practice. Key to addressing this threat is the discovery and development of new antibiotics that operate by unexploited modes of action. The so-called calcium-dependent lipopeptide antibiotics (CDAs) are an important emerging class of natural products that provides a source of new antibiotic agents rich in structural and mechanistic diversity. Notable in this regard is the subset of CDAs comprising the laspartomycins and amphomycins/friulimicins that specifically target the bacterial cell wall precursor undecaprenyl phosphate (C55-P). In this study we describe the design and synthesis of new C55-P-targeting CDAs with structural features drawn from both the laspartomycin and amphomycin/friulimicin classes. Assessment of these lipopeptides revealed previously unknown and surprisingly subtle structural features that are required for antibacterial activity. High-resolution crystal structures further indicate that the amphomycin/friulimicin-like lipopeptides adopt a unique crystal packing that governs their interaction with C55-P and provides an explanation for their antibacterial effect. In addition, live-cell microscopy studies provide further insights into the biological activity of the C55-P targeting CDAs highlighting their unique mechanism of action relative to the clinically used CDA daptomycin.Microbial Biotechnolog

Outcome of Patients After Transcatheter Aortic Valve Embolization

ObjectivesThis study aims to assess the mid- to long-term follow-up of patients after valve embolization at the time of transcatheter aortic valve implantation (TAVI).BackgroundTranscatheter heart valve (THV) embolization is a rare but serious complication during TAVI. Although various techniques have been developed to manage acute complications and reduce periprocedural morbidity/mortality, long-term clinical and hemodynamic consequences after these events are unknown.MethodsPatients who developed THV embolization after TAVI were prospectively assessed. Clinical and echocardiographic characteristics were recorded at baseline and after successful TAVI/surgical aortic valve replacement. The THV migration and strut fractures/degeneration were assessed by computed tomography.ResultsA total of 7 patients had THV embolization, all of which occurred immediately after valve deployment. The embolized THV was repositioned in the aortic arch proximal to the left subclavian artery (n = 2), immediately distal to the left subclavian artery (n = 2), and in the abdominal aorta (n = 3). A second THV was implanted successfully at the same sitting in 4 patients and at the time of a second procedure in 2 patients. Elective conventional aortic valve replacement was performed in 1 patient. Median follow-up was 1,085 days. One patient died during follow-up from an unrelated cause. The remaining 6 survivors were in New York Heart Association functional class I or II at final follow-up. Mid-term computed tomography follow-up (n = 4,591 to 1,548 days) showed that the leaflets of the embolized THV remain open in all phases of the cardiac cycle. There was also no strut fracture or migration of these valves.ConclusionsClinical outcomes remain good when THV embolization is managed effectively. There are no apparent hemodynamic consequences of a second valve placed in the series. These embolized valves remain in a stable position with no evidence of strut fractures at mid-term follow-up

Sensitivity of deexcitation energies of superdeformed secondary minima to the density dependence of symmetry energy with the relativistic mean-field theory

The relationship between deexcitation energies of superdeformed secondary minima relative to ground states and the density dependence of the symmetry energy is investigated for heavy nuclei using the relativistic mean field (RMF) model. It is shown that the deexcitation energies of superdeformed secondary minima are sensitive to differences in the symmetry energy that are mimicked by the isoscalar-isovector coupling included in the model. With deliberate investigations on a few Hg isotopes that have data of deexcitation energies, we find that the description for the deexcitation energies can be improved due to the softening of the symmetry energy. Further, we have investigated deexcitation energies of odd-odd heavy nuclei that are nearly independent of pairing correlations, and have discussed the possible extraction of the constraint on the density dependence of the symmetry energy with the measurement of deexcitation energies of these nuclei.Comment: 14 pages, 3 figure

Precise calculation of parity nonconservation in cesium and test of the standard model

We have calculated the 6s-7s parity nonconserving (PNC) E1 transition amplitude, E_{PNC}, in cesium. We have used an improved all-order technique in the calculation of the correlations and have included all significant contributions to E_{PNC}. Our final value E_{PNC} = 0.904 (1 +/- 0.5 %) \times 10^{-11}iea_{B}(-Q_{W}/N) has half the uncertainty claimed in old calculations used for the interpretation of Cs PNC experiments. The resulting nuclear weak charge Q_{W} for Cs deviates by about 2 standard deviations from the value predicted by the standard model.Comment: 24 pages, 8 figure

How Many CMEs Have Flux Ropes? Deciphering the Signatures of Shocks, Flux Ropes, and Prominences in Coronagraph Observations of CMEs

We intend to provide a comprehensive answer to the question on whether all Coronal Mass Ejections (CMEs) have flux rope structure. To achieve this, we present a synthesis of the LASCO CME observations over the last sixteen years, assisted by 3D MHD simulations of the breakout model, EUV and coronagraphic observations from STEREO and SDO, and statistics from a revised LASCO CME database. We argue that the bright loop often seen as the CME leading edge is the result of pileup at the boundary of the erupting flux rope irrespective of whether a cavity or, more generally, a 3-part CME can be identified. Based on our previous work on white light shock detection and supported by the MHD simulations, we identify a new type of morphology, the `two-front' morphology. It consists of a faint front followed by diffuse emission and the bright loop-like CME leading edge. We show that the faint front is caused by density compression at a wave (or possibly shock) front driven by the CME. We also present high-detailed multi-wavelength EUV observations that clarify the relative positioning of the prominence at the bottom of a coronal cavity with clear flux rope structure. Finally, we visually check the full LASCO CME database for flux rope structures. In the process, we classify the events into two clear flux rope classes (`3-part', `Loop'), jets and outflows (no clear structure). We find that at least 40% of the observed CMEs have clear flux rope structures. We propose a new definition for flux rope CMEs (FR-CMEs) as a coherent magnetic, twist-carrying coronal structure with angular width of at least 40 deg and able to reach beyond 10 Rsun which erupts on a time scale of a few minutes to several hours. We conclude that flux ropes are a common occurrence in CMEs and pose a challenge for future studies to identify CMEs that are clearly not FR-CMEs.Comment: 26 pages, 9 figs, to be published in Solar Physics Topical Issue "Flux Rope Structure of CMEs

Origin and Evolution of Saturn's Ring System

The origin and long-term evolution of Saturn's rings is still an unsolved problem in modern planetary science. In this chapter we review the current state of our knowledge on this long-standing question for the main rings (A, Cassini Division, B, C), the F Ring, and the diffuse rings (E and G). During the Voyager era, models of evolutionary processes affecting the rings on long time scales (erosion, viscous spreading, accretion, ballistic transport, etc.) had suggested that Saturn's rings are not older than 100 My. In addition, Saturn's large system of diffuse rings has been thought to be the result of material loss from one or more of Saturn's satellites. In the Cassini era, high spatial and spectral resolution data have allowed progress to be made on some of these questions. Discoveries such as the ''propellers'' in the A ring, the shape of ring-embedded moonlets, the clumps in the F Ring, and Enceladus' plume provide new constraints on evolutionary processes in Saturn's rings. At the same time, advances in numerical simulations over the last 20 years have opened the way to realistic models of the rings's fine scale structure, and progress in our understanding of the formation of the Solar System provides a better-defined historical context in which to understand ring formation. All these elements have important implications for the origin and long-term evolution of Saturn's rings. They strengthen the idea that Saturn's rings are very dynamical and rapidly evolving, while new arguments suggest that the rings could be older than previously believed, provided that they are regularly renewed. Key evolutionary processes, timescales and possible scenarios for the rings's origin are reviewed in the light of tComment: Chapter 17 of the book ''Saturn After Cassini-Huygens'' Saturn from Cassini-Huygens, Dougherty, M.K.; Esposito, L.W.; Krimigis, S.M. (Ed.) (2009) 537-57

Deep exclusive π+\pi^+ electroproduction off the proton at CLAS

The exclusive electroproduction of $\pi^+$ above the resonance region was studied using the $\rm{CEBAF}$ Large Acceptance Spectrometer ($\rm{CLAS}$) at Jefferson Laboratory by scattering a 6 GeV continuous electron beam off a hydrogen target. The large acceptance and good resolution of $\rm{CLAS}$, together with the high luminosity, allowed us to measure the cross section for the $\gamma^* p \to n \pi^+$ process in 140 ($Q^2$, $x_B$, $t$) bins: $0.16<x_B<0.58$, 1.6 GeV$^2<$$Q^2$$<4.5$ GeV$^2$ and 0.1 GeV$^2<$$-t$$<5.3$ GeV$^2$. For most bins, the statistical accuracy is on the order of a few percent. Differential cross sections are compared to two theoretical models, based either on hadronic (Regge phenomenology) or on partonic (handbag diagram) degrees of freedom. Both can describe the gross features of the data reasonably well, but differ strongly in their ingredients. If the handbag approach can be validated in this kinematical region, our data contain the interesting potential to experimentally access transversity Generalized Parton Distributions.Comment: 18pages, 21figures,2table

The spiritual organization: critical reflections on the instrumentality of workplace spirituality

Authors' draft of article. Final version published by Routledge in Journal of Management, Spirituality and Religion available online at: http://www.tandf.co.uk/journals/titles/14766086.aspThis paper offers a theoretical contribution to the current debate on workplace spirituality by: (a) providing a selective critical review of scholarship, research and corporate practices which treat workplace spirituality in performative terms, that is, as a resource or means to be manipulated instrumentally and appropriated for economic ends; (b) extending Ezioni’s analysis of complex organizations and proposing a new category, the ‘spiritual organization’, and; (c) positing three alternative positions with respect to workplace spirituality that follow from the preceding critique. The spiritual organization can be taken to represent the development of a trajectory of social technologies that have sought, incrementally, to control the bodies, minds, emotions and souls of employees. Alternatively, it might be employed to conceptualize the way in which employees use the workplace as a site for pursuing their own spiritualities (a reverse instrumentalism). Finally, we consider the possible incommensurability of ‘work organization’ and ‘spirituality’ discourses

Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial - study protocol for a multicentre randomised controlled trial

INTRODUCTION: Observational studies suggest both low and high iodine intakes in pregnancy are associated with poorer neurodevelopmental outcomes in children. This raises concern that current universal iodine supplement recommendations for pregnant women in populations considered to be iodine sufficient may negatively impact child neurodevelopment. We aim to determine the effect of reducing iodine intake from supplements for women who have adequate iodine intake from food on the cognitive development of children at 24 months of age. METHODS AND ANALYSIS: A multicentre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. Using a hybrid decentralised clinical trial model, 754 women (377 per group) less than 13 weeks' gestation with an iodine intake of ≥165 µg/day from food will be randomised to receive either a low iodine (20 µg/day) multivitamin and mineral supplement or an identical supplement containing 200) µg/day (amount commonly used in prenatal supplements in Australia), from enrolment until delivery. The primary outcome is the developmental quotient of infants at 24 months of age assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition. Secondary outcomes include infant language and motor development; behavioural and emotional development; maternal and infant clinical outcomes and health service utilisation of children. Cognitive scores will be compared between groups using linear regression, with adjustment for location of enrolment and the treatment effect described as a mean difference with 95% CI. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Research Ethics Committee (HREC/17/WCHN/187). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04586348.Karen P Best, Jacqueline F Gould, Maria Makrides, Thomas Sullivan, Jeanie Cheong, Shao J Zhou, Stefan Kane, Huda Safa, A Sparks, Lex W Doyle, A J McPhee, Tanya A C Nippita, Hossein H A Afzali, Rosalie Grivell, D Mackerras, E Knight, Simon Wood, Tim Gree