Suicide inhibition of alpha-oxamine synthases:structures of the covalent adducts of 8-amino-7-oxononanoate synthase with trifluoroalanine

The suicide inhibition of the α-oxamine synthases by the substrate analog, L-trifluoroalanine was investigated. The inhibition resulted in the formation of a complex with loss of all three fluorine atoms. Decarboxylation and loss of fluoride occurred immediately after aldimine formation. The inherent flexibility could allow the difluorinated intermediate complex to adopt a suitable conformation. Decarboxylation in the normal mechanism occurs after formation of the ketoacid intermediate.link_to_subscribed_fulltex

Cyclic Nucleotide-gated Ion Channels in Rod Photoreceptors Are Protected from Retinoid Inhibition

In vertebrate rods, photoisomerization of the 11-cis retinal chromophore of rhodopsin to the all-trans conformation initiates a biochemical cascade that closes cGMP-gated channels and hyperpolarizes the cell. All-trans retinal is reduced to retinol and then removed to the pigment epithelium. The pigment epithelium supplies fresh 11-cis retinal to regenerate rhodopsin. The recent discovery that tens of nanomolar retinal inhibits cloned cGMP-gated channels at low [cGMP] raised the question of whether retinoid traffic across the plasma membrane of the rod might participate in the signaling of light. Native channels in excised patches from rods were very sensitive to retinoid inhibition. Perfusion of intact rods with exogenous 9- or 11-cis retinal closed cGMP-gated channels but required higher than expected concentrations. Channels reopened after perfusing the rod with cellular retinoid binding protein II. PDE activity, flash response kinetics, and relative sensitivity were unchanged, ruling out pharmacological activation of the phototransduction cascade. Bleaching of rhodopsin to create all-trans retinal and retinol inside the rod did not produce any measurable channel inhibition. Exposure of a bleached rod to 9- or 11-cis retinal did not elicit channel inhibition during the period of rhodopsin regeneration. Microspectrophotometric measurements showed that exogenous 9- or 11-cis retinal rapidly cross the plasma membrane of bleached rods and regenerate their rhodopsin. Although dark-adapted rods could also take up large quantities of 9-cis retinal, which they converted to retinol, the time course was slow. Apparently cGMP-gated channels in intact rods are protected from the inhibitory effects of retinoids that cross the plasma membrane by a large-capacity buffer. Opsin, with its chromophore binding pocket occupied (rhodopsin) or vacant, may be an important component. Exceptionally high retinoid levels, e.g., associated with some retinal degenerations, could overcome the buffer, however, and impair sensitivity or delay the recovery after exposure to bright light

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Mechanical evaluation of electrospun poly(ε-caprolactone) single fibers

In the scope of biomechanical applications of electrospun polymer microfibers, a new method for testing single electrospun microfibers was used to reliably establish mechanical properties of poly(ε-caprolactone) microfibers within a wide range of diameters from 0.4–6.0 μm. Cyclic mechanical tests were used to establish a bimodal linear relationship between fiber diameter and Young’s modulus. An inflection point was found at approximately 0.9 μm, where a sharp increase in modulus below this diameter was observed. The abrupt rise in modulus was not observed on the same scale in scaffolds produced with corresponding fibers and could not be explained only through a change in crystallinity of the polymer. Furthermore, the elastically recovered strain was assessed at maximum strain up to 20 %. It was found that polycaprolactone exhibits a viscoelastic range up to 13.17 ± 3.1 % after preconditioning, which is sufficient for most relevant biomechanical applications

Mechanical and biological characterization of a composite annulus fibrosus repair strategy in an endplate delamination model

This study compares the mechanical response of the commonly used annulus fibrosus (AF) puncture injury model of the intervertebral disc (IVD) and a newly proposed AF failure at the endplate junction (delamination) on ex vivo bovine IVDs. Biocompatibility and mechanics of a newly developed repair strategy comprising of electrospun polycaprolactone (PCL) scaffold and fibrin‐genipin (FibGen) adhesive was tested on the delamination model. The study found no significant difference in the mechanical response to compressive loading between the two models. Primary goals of the repair strategy to create a tight seal on the damage area and restore mechanical properties, while showing minimal cytotoxicity, were broadly achieved. Postrepair, the IVDs showed a significant restoration of mechanical properties compared to the injured samples for the delamination model. The FibGen glue showed a limited toxicity in the AF and produced a resilient and mechanically stable seal on the damaged area.ISSN:2572-114

Learning to school in the presence of hydrodynamic interactions

Schooling, an archetype of collective behaviour, emerges from the interactions of fish responding to sensory information mediated by their aqueous environment. A fundamental and largely unexplored question in fish schooling concerns the role of hydrodynamics. Here, we investigate this question by modelling swimmers as vortex dipoles whose interactions are governed by the Biot–Savart law. When we enhance these dipoles with behavioural rules from classical agent-based models, we find that they do not lead robustly to schooling because of flow-mediated interactions. We therefore propose to use swimmers equipped with adaptive decision-making that adjust their gaits through a reinforcement learning algorithm in response to nonlinearly varying hydrodynamic loads. We demonstrate that these swimmers can maintain their relative position within a formation by adapting their strength and school in a variety of prescribed geometrical arrangements. Furthermore, we identify schooling patterns that minimize the individual and collective swimming effort, through an evolutionary optimization. The present work suggests that the adaptive response of individual swimmers to flow-mediated interactions is critical in fish schooling.ISSN:0022-1120ISSN:1469-764