Post-translational modification of therapeutic peptides by NisB, the dehydratase of the lantibiotic nisin

Post-translationally introduced dehydroamino acids often play an important role in the activity and receptor specificity of biologically active peptides. In addition, a dehydroamino acid can be coupled to a cysteine to yield a cyclized peptide with increased biostability and resistance against proteolytic degradation and/or modified specificity. The lantibiotic nisin is an antimicrobial peptide produced by Lactococcus lactis. Its post-translational enzymatic modification involves NisB-mediated dehydration of serines and threonines and NisC-catalyzed coupling of cysteines to dehydroresidues, followed by NisT-mediated secretion. Here, we demonstrate that a L. lactis strain containing the nisBTC genes effectively dehydrates and secretes a wide range of medically relevant nonlantibiotic peptides among which variants of adrenocorticotropic hormone, vasopressin, an inhibitor of tripeptidyl peptidase II, enkephalin, luteinizing hormone-releasing hormone, angiotensin, and erythropoietin. For most of these peptides, ring formation was demonstrated. These data show that lantibiotic enzymes can be applied for the modification of peptides, thereby enabling the biotechnological production of dehydroresidue-containing and/or thioether-bridged therapeutic peptides with enhanced stability and/or modulated activities.</p

Multiple backscattering in trivial and non-trivial topological photonic crystal edge states with controlled disorder

We present an experimental investigation of multiple scattering in photonic-crystal-based topological edge states with and without engineered random disorder. We map the spatial distribution of light as it propagates along a so-called bearded interface between two valley photonic crystals which supports both trivial and non-trivial edge states. As the light slows down and/or the disorder increases, we observe the photonic manifestation of Anderson localization, illustrated by the appearance of localized high-intensity field distributions. We extract the backscattering mean free path (BMFP) as a function of frequency, and thereby group velocity, for a range of geometrically engineered random disorders of different types. For relatively high group velocities (with $n_g < 15$), we observe that the BMFP is an order of magnitude higher for the non-trivial edge state than for the trivial. However, the BMFP for the non-trivial mode decreases rapidly with increasing disorder. As the light slows down the BMFP for the trivial state decreases as expected, but the BMFP for the topological state exhibits a non-conventional dependence on the group velocity. Due to the particular dispersion of the topologically non-trivial mode, a range of frequencies exist where two distinct states can have the same group index but exhibit a different BMFP. While the topological mode is not immune to backscattering at disorder that breaks the protecting crystalline symmetry, it displays a larger robustness than the trivial mode for a specific range of parameters in the same structure. Intriguingly, the topologically non-trivial edge state appears to break the conventional relationship between slowdown and the amount of backscattering.Comment: 16 pages, 12 figure

Semiclassical expansion of parametric correlation functions of the quantum time delay

We derive semiclassical periodic orbit expansions for a correlation function of the Wigner time delay. We consider the Fourier transform of the two-point correlation function, the form factor $K(\tau,x,y,M)$, that depends on the number of open channels $M$, a non-symmetry breaking parameter $x$, and a symmetry breaking parameter $y$. Several terms in the Taylor expansion about $\tau=0$, which depend on all parameters, are shown to be identical to those obtained from Random Matrix Theory.Comment: 21 pages, no figure

Effective elements of cognitive behaviour therapy for psychosis: results of a novel type of subgroup analysis based on principal stratification

Background. Meta-analyses show that cognitive behaviour therapy for psychosis (CBT-P) improves distressing positive symptoms. However, it is a complex intervention involving a range of techniques. No previous study has assessed the delivery of the different elements of treatment and their effect on outcome. Our aim was to assess the differential effect of type of treatment delivered on the effectiveness of CBT-P, using novel statistical methodology. Method. The Psychological Prevention of Relapse in Psychosis (PRP) trial was a multi-centre randomized controlled trial (RCT) that compared CBT-P with treatment as usual (TAU). Therapy was manualized, and detailed evaluations of therapy delivery and client engagement were made. Follow-up assessments were made at 12 and 24 months. In a planned analysis, we applied principal stratification (involving structural equation modelling with finite mixtures) to estimate intention-to-treat (ITT) effects for subgroups of participants, defined by qualitative and quantitative differences in receipt of therapy, while maintaining the constraints of randomization. Results. Consistent delivery of full therapy, including specific cognitive and behavioural techniques, was associated with clinically and statistically significant increases in months in remission, and decreases in psychotic and affective symptoms. Delivery of partial therapy involving engagement and assessment was not effective. Conclusions. Our analyses suggest that CBT-P is of significant benefit on multiple outcomes to patients able to engage in the full range of therapy procedures. The novel statistical methods illustrated in this report have general application to the evaluation of heterogeneity in the effects of treatment

Semiclassical Approach to Chaotic Quantum Transport

We describe a semiclassical method to calculate universal transport properties of chaotic cavities. While the energy-averaged conductance turns out governed by pairs of entrance-to-exit trajectories, the conductance variance, shot noise and other related quantities require trajectory quadruplets; simple diagrammatic rules allow to find the contributions of these pairs and quadruplets. Both pure symmetry classes and the crossover due to an external magnetic field are considered.Comment: 33 pages, 11 figures (appendices B-D not included in journal version

Multi-Layer Cyber-Physical Security and Resilience for Smart Grid

The smart grid is a large-scale complex system that integrates communication technologies with the physical layer operation of the energy systems. Security and resilience mechanisms by design are important to provide guarantee operations for the system. This chapter provides a layered perspective of the smart grid security and discusses game and decision theory as a tool to model the interactions among system components and the interaction between attackers and the system. We discuss game-theoretic applications and challenges in the design of cross-layer robust and resilient controller, secure network routing protocol at the data communication and networking layers, and the challenges of the information security at the management layer of the grid. The chapter will discuss the future directions of using game-theoretic tools in addressing multi-layer security issues in the smart grid.Comment: 16 page

Nothing moves a surface: vacancy mediated surface diffusion

We report scanning tunneling microscopy observations, which imply that all atoms in a close-packed copper surface move frequently, even at room temperature. Using a low density of embedded indium `tracer' atoms, we visualize the diffusive motion of surface atoms. Surprisingly, the indium atoms seem to make concerted, long jumps. Responsible for this motion is an ultra-low density of surface vacancies, diffusing rapidly within the surface. This interpretation is supported by a detailed analysis of the displacement distribution of the indium atoms, which reveals a shape characteristic for the vacancy mediated diffusion mechanism that we propose.Comment: 4 pages; for associated movie, see http://www-lion.leidenuniv.nl/sections/cm/groups/interface/projects/therm