Resolution requirements for numerical simulations of transition

The resolution requirements for direct numerical simulations of transition to turbulence are investigated. A reliable resolution criterion is determined from the results of several detailed simulations of channel and boundary-layer transition

Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in Staphylococcus aureus

Mannitol-1-phosphate dehydrogenase (M1PDH) is a key enzyme in Staphylococcus aureus mannitol metabolism, but its roles in pathophysiological settings have not been established. We performed comprehensive structure-function analysis of M1PDH from S. aureus USA300, a strain of community-associated methicillin-resistant S. aureus, to evaluate its roles in cell viability and virulence under pathophysiological conditions. On the basis of our results, we propose M1PDH as a potential antibacterial target. In vitro cell viability assessment of ΔmtlD knockout and complemented strains confirmed that M1PDH is essential to endure pH, high-salt, and oxidative stress and thus that M1PDH is required for preventing osmotic burst by regulating pressure potential imposed by mannitol. The mouse infection model also verified that M1PDH is essential for bacterial survival during infection. To further support the use of M1PDH as an antibacterial target, we identified dihydrocelastrol (DHCL) as a competitive inhibitor of S. aureus M1PDH (SaM1PDH) and confirmed that DHCL effectively reduces bacterial cell viability during host infection. To explain physiological functions of SaM1PDH at the atomic level, the crystal structure of SaM1PDH was determined at 1.7-Å resolution. Structure-based mutation analyses and DHCL molecular docking to the SaM1PDH active site followed by functional assay identified key residues in the active site and provided the action mechanism of DHCL. Collectively, we propose SaM1PDH as a target for antibiotic development based on its physiological roles with the goals of expanding the repertory of antibiotic targets to fight antimicrobial resistance and providing essential knowledge for developing potent inhibitors of SaM1PDH based on structure-function studies.IMPORTANCE Due to the shortage of effective antibiotics against drug-resistant Staphylococcus aureus, new targets are urgently required to develop next-generation antibiotics. We investigated mannitol-1-phosphate dehydrogenase of S. aureus USA300 (SaM1PDH), a key enzyme regulating intracellular mannitol levels, and explored the possibility of using SaM1PDH as a target for developing antibiotic. Since mannitol is necessary for maintaining the cellular redox and osmotic potential, the homeostatic imbalance caused by treatment with a SaM1PDH inhibitor or knockout of the gene encoding SaM1PDH results in bacterial cell death through oxidative and/or mannitol-dependent cytolysis. We elucidated the molecular mechanism of SaM1PDH and the structural basis of substrate and inhibitor recognition by enzymatic and structural analyses of SaM1PDH. Our results strongly support the concept that targeting of SaM1PDH represents an alternative strategy for developing a new class of antibiotics that cause bacterial cell death not by blocking key cellular machinery but by inducing cytolysis and reducing stress tolerance through inhibition of the mannitol pathway

All-optical Compton scattering at shallow interaction angles

All-optical Compton sources combine laser wakefield accelerators and intense scattering pulses to generate ultrashort bursts of backscattered radiation. The scattering pulse plays the role of a short-period undulator in which relativistic electrons oscillate and emit x-ray radiation. To date, most of the working laser-plasma accelerators operate preferably at energies of a few hundreds of MeV and the Compton sources developed so far produce radiation in the range from hundreds of keV to a few MeV. However, for such applications as medical imaging and tomography the relevant energy range is 10-100 keV. In this article, we discuss different scattering geometries for the generation of X-rays in this range. Through numerical simulations, we study the influence of electron beam parameters on the backscattered photons. We find that the spectral bandwidth remains constant for beams of the same emittance regardless of the scattering geometry. A shallow interaction angle of 30 degrees or less seems particularly promising for imaging applications given parameters of existing laser-plasma accelerators. Finally, we discuss the influence of the radiation properties for potential applications in medical imaging and non-destructive testing

Measurements and calculations of transport AC loss in second generation high temperature superconducting pancake coils

Theoretical and experimental AC loss data on a superconducting pancake coil wound using second generation (2 G) conductors are presented. An anisotropic critical state model is used to calculate critical current and the AC losses of a superconducting pancake coil. In the coil there are two regions, the critical state region and the subcritical region. The model assumes that in the subcritical region the flux lines are parallel to the tape wide face. AC losses of the superconducting pancake coil are calculated using this model. Both calorimetric and electrical techniques were used to measure AC losses in the coil. The calorimetric method is based on measuring the boil-off rate of liquid nitrogen. The electric method used a compensation circuit to eliminate the inductive component to measure the loss voltage of the coil. The experimental results are consistent with the theoretical calculations thus validating the anisotropic critical state model for loss estimations in the superconducting pancake coil

An Algorithm for the Continuous Morlet Wavelet Transform

This article consists of a brief discussion of the energy density over time or frequency that is obtained with the wavelet transform. Also an efficient algorithm is suggested to calculate the continuous transform with the Morlet wavelet. The energy values of the Wavelet transform are compared with the power spectrum of the Fourier transform. Useful definitions for power spectra are given. The focus of the work is on simple measures to evaluate the transform with the Morlet wavelet in an efficient way. The use of the transform and the defined values is shown in some examples.Comment: 15 pages, 4 figures, revised for MSS

Leadership styles and safety performance in high-risk industries: a systematic review

The importance of leadership on safety has been well acknowledged and studied for many years in various high-risk industries. This paper aims at (1) synthesising the existing safety leadership research by performing a systematic literature review to gain an overview of the relationship between various leadership styles and safety performance in high-risk industries with a main focus on health and workplace safety and (2) analysing and comparing the major results from the reviewed studies. The results show that nine leadership styles – transformational leadership, transactional leadership, leader–member exchange, authentic leadership, empowering leadership, ethical leadership, paternalistic leadership, charismatic leadership and passive leadership – have been frequently used in the development and validation of safety leadership theories as well as in understanding the leadership influence towards safety climate, safety compliance and safety participation in various contexts. However, blurred boundaries among the constructs of leadership styles alongside inconsistency in the conceptualisation and measurement of safety performance hinder the advancement of understanding safety leadership’s influence on safety performance. It is therefore of importance that further research develops consistent measurement instruments and conceptualisation and that systems thinking is applied to the study of leadership styles’ influence on safety performance.publishedVersio

Regulation of Antimycin Biosynthesis Is Controlled by the ClpXP Protease

The survival of any microbe relies on its ability to respond to environmental change. Use of extracytoplasmic function (ECF) RNA polymerase sigma (σ) factors is a major strategy enabling dynamic responses to extracellular signals. Streptomyces species harbor a large number of ECF σ factors, nearly all of which are uncharacterized, but those that have been characterized generally regulate genes required for morphological differentiation and/or response to environmental stress, except for σAntA, which regulates starter-unit biosynthesis in the production of antimycin, an anticancer compound. Unlike a canonical ECF σ factor, whose activity is regulated by a cognate anti-σ factor, σAntA is an orphan, raising intriguing questions about how its activity may be controlled. Here, we reconstituted in vitro ClpXP proteolysis of σAntA but not of a variant lacking a C-terminal di-alanine motif. Furthermore, we show that the abundance of σAntA in vivo was enhanced by removal of the ClpXP recognition sequence and that levels of the protein rose when cellular ClpXP protease activity was abolished. These data establish direct proteolysis as an alternative and, thus far, unique control strategy for an ECF RNA polymerase σ factor and expands the paradigmatic understanding of microbial signal transduction regulation