Activation,Structure, Biosynthesis and Bioactivity of Glidobactin-like Proteasome Inhibitors from Photorhabdus laumondii

The glidobactin-like natural products (GLNPs) glidobactin A and cepafungin I have been reported to be potent proteasome inhibitors and are regarded as promising candidates for anticancer drug development. Their biosynthetic gene cluster (BGC) plu1881–1877 is present in entomopathogenic Photorhabdus laumondii but silent under standard laboratory conditions. Here we show the largest subset of GLNPs, which are produced and identified after activation of the silent BGC in the native host and following heterologous expression of the BGC in Escherichia coli. Their chemical diversity results from a relaxed substrate specificity and flexible product release in the assembly line of GLNPs. Crystal structure analysis of the yeast proteasome in complex with new GLNPs suggests that the degree of unsaturation and the length of the aliphatic tail are critical for their bioactivity. The results in this study provide the basis to engineer the BGC for the generation of new GLNPs and to optimize these natural products resulting in potential drugs for cancer therapy.     

Sagittal plane lumbar loading when navigating an obstacle and carrying a load

The current study quantified lumbar loading while carrying an anterior load mass and navigating an obstacle. Eight healthy male participants walked down a walkway and crossed an obstacle under three randomised LOAD conditions; empty-box (2 KG), five kilogram (5 KG) and ten kilogram (10 KG). Each walk was assessed at two events: left foot mid-stance (LMS) and right toe-crossing (TC) to characterise any changes from approach to crossing. Measures of interest included: trunk pitch, L4/L5 joint moment, compression, joint anterior–posterior shear and erector spinae activation. Findings demonstrate that obstacle crossing extended posture by 50, 41, 44%, respectively for each carried load magnitude. Further, these results indicate that shear rather than compressive loading may be an important consideration during crossing due to increase by 8, 9, 22% from LMS to TC for each load magnitude tested. These results provide insight into sagittal lumbar loading when navigating an obstacle while carrying a load.

Practitioner Summary: The risk of carrying while navigating obstacles on the lumbar spine is not completely understood. The forces at the lumbar spine while simultaneously carrying and obstacle crossing were analysed. Data indicate that carrying and obstacle crossing influence lumbar shear loads, thereby moderately increasing the relative risk at lumbar spine.     

Extensible Auditory Progress Bar Design: Performance and Aesthetics

This study investigated performance and preference differences for three different extensible Auditory Progress Bar (APB) designs. Four durations (30 s, 60 s, 120 s, 240 s) of the three APBs (Sine, Cello, and Electronic) were used in the study. There were 105 participants who listened to all durations of a single-stimulus type and were asked to determine the length of time they had listened to the stimulus and to rate the stimuli on aesthetic quality. Participants were significantly worse at time estimation with the Electronic APB. The Sine APB was preferred significantly less than either the Cello or Electronic APBs. Regardless of the stimulus, time estimation was more variable and more accurate as the duration of the APB increased. The results indicate that although they were originally envisioned as a supplement for the visual progress bar, APBs can be effective when used alone. Further, it was found that, even within the small design space presented here, APB design can influence the performance of listeners.     

Electrodissolution de la galène en présence d'une induction magnétique inhomogéne

Résumé La polarisation anodique des sulfure de plomb en présence et en l'absence d'un champ magnétique a été étudiée en milieu d'acide chlorhydrique 1 mol dm^–3 à la temperature ambiante. Le courant anodique est sensible à la présence d'un champ magnétique inhomogène. Les études potentiocinétique et potentiostatique concernant l'influence de l'induction magnétique sur le courant montrent un comportement différent suivant la magnitude du champ. En choisissant certaines conditions expérimentales, le courant stationnaire à potentiel imposé peut être multiplié par un facteur de 1.5–1.8.

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The anodic polarisation of lead sulphide with and without a magnetic field has been studied in hydrochloric acid medium, 1 mol dm^–3, at ambient temperature. The anodic current is sensitive to the presence of a heterogeneous magnetic field. The potentiodynamic and potentiostatic studies concerning the influence of the magnetic induction on the current show a different behaviour for different magnitudes of the field. In choosing certain experimental conditions, the stationary current at an imposed potential can be multiplied by a factor of 1.5–1.8.

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On leave from Laboratoire d'Electrochimie, Université de Reims, BP 347-51062 Reims Cédex, France. Visiting Professor at l'Université Laval in 1981.     

Assessment of Isoprostanes in Human Plasma: Technical Considerations and the Use of Mass Spectrometry

Oxygenated lipid mediators released from non‐enzymatic peroxidation of polyunsaturated fatty acids (PUFA) are known to have functional roles in humans. Notably, among these lipid mediators, isoprostanes molecules are robust biomarkers of oxidative stress but those from n‐3 PUFA are also bioactive molecules. In order to identify and assess the isoprostanes, the use of mass spectrometry (MS) for analysis is preferable and has been used for over two decades. Gas chromatography (GC) is commonly coupled to the MS to separate the derivatized isoprostanes of interest in biological samples. In order to increase the accuracy of the analytical performance, GC–MS/MS was also applied. Lately, MS or MS/MS has been coupled with high‐performance liquid chromatography to assess multiple isoprostane molecules in a single biological sample without derivatization process. However, there are limitations for the use of LC–MS/MS in the measurement of plasma isoprostanes, which will be discussed in this review.     

Auxetic Cardiac Patches with Tunable Mechanical and Conductive Properties toward Treating Myocardial Infarction

An auxetic conductive cardiac patch (AuxCP) for the treatment of myocardial infarction (MI) is introduced. The auxetic design gives the patch a negative Poisson's ratio, providing it with the ability to conform to the demanding mechanics of the heart. The conductivity allows the patch to interface with electroresponsive tissues such as the heart. Excimer laser microablation is used to micropattern a re‐entrant honeycomb (bow‐tie) design into a chitosan‐polyaniline composite. It is shown that the bow‐tie design can produce patches with a wide range in mechanical strength and anisotropy, which can be tuned to match native heart tissue. Further, the auxetic patches are conductive and cytocompatible with murine neonatal cardiomyocytes in vitro. Ex vivo studies demonstrate that the auxetic patches have no detrimental effect on the electrophysiology of both healthy and MI rat hearts and conform better to native heart movements than unpatterned patches of the same material. Finally, the AuxCP applied in a rat MI model results in no detrimental effect on cardiac function and negligible fibrotic response after two weeks in vivo. This approach represents a versatile and robust platform for cardiac biomaterial design and could therefore lead to a promising treatment for MI.     

Why is it so difficult to realize Dy4+ in as-synthesized BaZrO3?

Rare-earth doped barium zirconate (BaZrO₃) ceramics are of interest as proton-conducting and luminescent materials. Here, we report a study of dysprosium (Dy) and other relevant point defects in BaZrO₃ using hybrid density-functional defect calculations. The tetravalent Dy⁴⁺ is found to be structurally and electronically stable at the Zr lattice site (i.e., as Dy_Zr⁰), but most often energetically less favorable than the trivalent Dy³⁺ (i.e., Dy_Zr^–) in as-synthesized BaZrO₃, due to the formation of low-energy, positively charged oxygen vacancies and the mixed-site occupancy of Dy in the host lattice. The Dy⁴⁺/Dy³⁺ ratio can, in principle, be increased by preparing the material under highly oxidizing and Ba-rich conditions and co-doping with acceptor-like impurities; however, a post-synthesis treatment may still be needed to realize a nonnegligible Dy⁴⁺ concentration. We also find that certain unoccupied Dy 4f states and the O 2p states in the Dy_Zr⁰ configuration are strongly hybridized, a feature not often seen in rare-earth-containing materials, and that the isolated Dy_Zr defect might be the source of a broad blue emission in band-to-defect (“charge-transfer”) luminescence.     

Precise,efficient, and context-sensitive cache analysis

Real-Time Systems - Bounding the Worst-Case Execution Time (WCET) of real-time software requires precise knowledge about the reachable program and hardware states that might be observed at runtime....     

Development of mesoporous bioactive glass-containing macroporous titanium for controlled release of antimicrobial drugs

Biofilm-associated infections pose a serious threat to the long-term survival of metal-based bone implants, which can potentially be resolved by the controlled delivery of antimicrobial agents locally at the implant surface. Mesoporous bioactive glasses (BAGs) are multifunctional materials able to combine bone-bonding properties with such a drug release functionality. Here, we propose for the first time to modify a macroporous Ti implant material with an antimicrobial-releasing BAG phase. The feasibility of a sol-gel synthesis route, including the structure-directing agent (SDA) Pluronic F127, and its effect on the mesoporous structure and concomitant drug release performance was evaluated. Mesopore sizes ranged from 3.4 nm for SDA-free to 3.7 nm for SDA-derived BAG, thereby both enabling configurational diffusion of the antiseptic chlorhexidine (CHX), but the latter showed a more narrow pore size distribution leading to a slower, more controlled release. Adjusting the feed concentration allowed fine-tuning the daily CHX release through the SDA-derived Ti/BAG composite to 1.4 μM. Even though just below the biofilm inhibitory concentration, this daily release rate was sufficient to effectively prevent Streptococcus mutans biofilm formation on the surface of the material. This proof-of-concept for a temporary antimicrobial-releasing bioceramic surface modification on Ti can be of interest for orthopedic implants.