Abstract. The Fourth IPCC Assessment Report concluded that ice sheet flow models, in their current state, were unable to provide accurate forecast for the increase of polar ice sheet discharge and the associated contribution to sea level rise. Since then, the glaciological community has undertaken a huge effort to develop and improve a new generation of ice flow models, and as a result a significant number of new ice sheet models have emerged. Among them is the parallel finite-element model Elmer/Ice, based on the opensource multi-physics code Elmer. It was one of the first fullStokes models used to make projections for the evolution of the whole Greenland ice sheet for the coming two centuries. Originally developed to solve local ice flow problems of high mechanical and physical complexity, Elmer/Ice has today reached the maturity to solve larger-scale problems, earning the status of an ice sheet model. Here, we summarise almost 10 yr of development performed by different groups. Elmer/Ice solves the full-Stokes equations, for isotropic but also anisotropic ice rheology, resolves the grounding line dynamics as a contact problem, and contains various basal friction laws. Derived fields, like the age of the ice, the strain rate or stress, can also be computed. Elmer/Ice includes two recently proposed inverse methods to infer badly known parameters. Elmer is a highly parallelised code thanks to recent developments and the implementation of a block preconditioned solver for the Stokes system. In this paper, all these components are presented in detail, as well as the numerical performance of the Stokes solver and developments planned for the future.

The crystal structures of the human androgen receptor (hAR) and human progesterone receptor ligandbinding domains in complex with the same ligand metribolone (R1881) have been determined. Both threedimensional structures show the typical nuclear receptor fold. The change of two residues in the ligandbinding pocket between the human progesterone receptor and hAR is most likely the source for the specificity of R1881 to the hAR. The structural implications of the 14 known mutations in the ligand-binding pocket of the hAR ligand-binding domains associated with either prostate cancer or the partial or complete androgen receptor insensitivity syndrome were analyzed. The effects of most of these mutants could be explained on the basis of the crystal structure. Androgen (AR)1 and progesterone receptors (PR) are members of the superfamily of nuclear receptors that includes the steroid receptors, among others, as well as the vitamin D, thyroid, retinoic acid receptors, and the so-called orphan receptors. In addition, AR and PR are members of a group of four closely related steroid receptors including the mineralocorticoid receptor and the glucocorticoid receptor recognizing the same hormone response element. In general, steroid receptors are comprised of five to six domains and act as ligand-activated transcription factors that control the expression of specific genes. To date, no experimentally determined three-dimensional structure is available for a complete receptor. During the past few years, x-ray structures have been published for two of the domains, the DNA-binding domain as well as for a number of ligand-binding domains (LBD) including LBD⅐ligand complexes of the estrogen receptor ␣ and ␤, the PR, the vitamin D receptor, the retinoic acid receptors (X,RXR; acid, RAR), the thyroid hormone receptor, and the peroxisome proliferatoractivated receptors (1-13). Despite the low sequence homology of as low as 20% between the LBDs of different nuclear receptor families, all these proteins share a similar fold. They are comprised of up to 12 helices and a small ␤-sheet arranged in a so-called ␣-helical sandwich, a kind of fold that up to now has only been observed for the LBDs of nuclear receptors. Depending on the nature of the bound ligand, agonist, or antagonist, the carboxyl-terminal helix H12 is found in either one of two orientations. In the agonist-bound conformation, helix H12 serves as a "lid" to close the ligand-binding pocket (LBP), whereas in the antagonist-bound conformation helix H12 is positioned in a different orientation thus opening the entrance to the LBP.Androgens and their receptors play an important role in male physiology and pathology.

The vasodilatory properties of nitric oxide (NO) have been utilized in pharmacotherapy for more than 130 years. Still today, NO-donor drugs are important in the management of cardiovascular diseases. However, inhaled NO or drugs releasing NO and organic nitrates are associated with noteworthy therapeutic shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and nonspecific effects, such as post-translational modification of proteins. The beneficial actions of NO are mediated by stimulation of soluble guanylate cyclase (sGC), a heme-containing enzyme which produces the intracellular signaling molecule cyclic guanosine monophosphate (cGMP). Recently, two classes of compounds have been discovered that amplify the function of sGC in a NO-independent manner, the so-called sGC stimulators and sGC activators. The most advanced drug, the sGC stimulator riociguat, has successfully undergone Phase III clinical trials for different forms of pulmonary hypertension.

Our structure confirms that vancomycin exists as an asymmetric dimer. The dimer conformation allows the docking of two D-Ala-D-Ala peptides in opposite directions; these presumably would be attached to different glycopeptide strands. In the crystal, one of the binding pockets is occupied by an acetate ion that mimics the C terminus of the nascent cell wall peptide; the other is closed by the asparagine sidechain, which occupies the place of a ligand. The occupied binding pocket exhibits high flexibility but the closed binding pocket is relatively rigid. We propose that the asparagine sidechain may hold the binding pocket in a suitable conformation for peptide docking, swinging out of the way when the peptide enters the binding pocket.

The Fourth IPCC Assessment Report concluded that ice-sheet flow models are unable to forecast the current increase of polar ice sheet discharge and the associated contribution to sea-level rise. Since then, the glaciological community has undertaken a huge effort to develop and improve a new generation of ice-flow models, and as a result, a significant number of new ice-sheet models have emerged. Among them is the parallel finite-element model Elmer/Ice, based on the open-source multi-physics code Elmer. It was one of the first full-Stokes models used to make projections for the evolution of the whole Greenland ice sheet for the coming two centuries. Originally developed to solve local ice flow problems of high mechanical and physical complexity, Elmer/Ice has today reached the maturity to solve larger scale problems, earning the status of an ice-sheet model. Here, we summarise almost 10 yr of development performed by different groups. We present the components already included in Elmer/Ice, its numerical performance, selected applications, as well as developments planned for the future