Solitary waves in the Nonlinear Dirac Equation

In the present work, we consider the existence, stability, and dynamics of solitary waves in the nonlinear Dirac equation. We start by introducing the Soler model of self-interacting spinors, and discuss its localized waveforms in one, two, and three spatial dimensions and the equations they satisfy. We present the associated explicit solutions in one dimension and numerically obtain their analogues in higher dimensions. The stability is subsequently discussed from a theoretical perspective and then complemented with numerical computations. Finally, the dynamics of the solutions is explored and compared to its non-relativistic analogue, which is the nonlinear Schr{\"o}dinger equation. A few special topics are also explored, including the discrete variant of the nonlinear Dirac equation and its solitary wave properties, as well as the PT-symmetric variant of the model

Mass loss from hot massive stars

Mass loss is a key process in the evolution of massive stars, and must be understood quantitatively to be successfully included in broader astrophysical applications. In this review, we discuss various aspects of radiation driven mass loss, both from the theoretical and the observational side. We focus on winds from OB-stars, with some excursions to the Luminous Blue Variables, Wolf- Rayet stars, A-supergiants and Central Stars of Planetary Nebulae. After reca- pitulating the 1-D, stationary standard model of line-driven wind, extensions accounting for rotation and magnetic fields are discussed. The relevance of the so-called bi-stability jump is outlined. We summarize diagnostical methods to infer wind properties from observations, and compare the results with theore- tical predictions, featuring the massloss-metallicity dependence. Subsequently, we concentrate on two urgent problems which challenge our present understanding of radiation driven winds: weak winds and wind- clumping. We discuss problems of measuring mass-loss rates from weak winds and the potential of NIR- spectroscopy. Wind-clumping has severe implications for the interpretation of observational diagnostics, as derived mass-loss rates can be overestimated by factors of 2 to 10 if clumping is ignored, and we describe ongoing attempts to allow for more uniform results. We point out that independent arguments from stellar evolution favor a moderate reduction of present- day mass-loss rates. We also consider larger scale wind structure, interpreted in terms of co-rotating interacting regions, and complete this review with a discussion of recent progress on the X-ray line emission from massive stars, highlighting as to how far the analysis of such X-ray line emission can give further clues regarding an adequate description of wind clumping. (Abridged abstract)Comment: Astronomy and Astrophysics Review (accepted

Exposing Hidden Alternative Backbone Conformations in X-ray Crystallography Using qFit

Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechain conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the "flap" regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Overall, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems

Novel therapeutic targets in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis. It results in characteristic symptoms with marked effects on life quality. The advent of large patient cohorts has challenged the view of PBC as a benign condition treated effectively by the single licensed therapy-ursodeoxycholic acid ( UDCA). UDCA nonresponse or under-response has a major bearing on outcome, substantially increasing the likelihood that liver transplantation will be required or that patients will die of the disease. In patients with high-risk, treatment-unresponsive or highly symptomatic disease the need for new treatment approaches is clear. Evolution in our understanding of disease mechanisms is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. Notable opportunities are offered by targeting what could be considered as the 'upstream' immune response, 'midstream' biliary injury and 'downstream' fibrotic processes. Combination therapy targeting several pathways or the development of novel agents addressing multiple components of the disease pathway might be required. Ultimately, PBC therapeutics will require a stratified approach to be adopted in practice. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatment