With the increasing prevalence of end stage renal disease there is a growing need for hemodialysis. Arteriovenous fistulae (AVF) are the preferred type of vascular access for hemodialysis but maturation and failure continue to present significant barriers to successful fistula use. AVF maturation integrates outward remodeling with vessel wall thickening in response to drastic hemodynamic changes, in the setting of uremia, systemic inflammation, oxidative stress and preexistent vascular pathology. AVF can fail due to both failure to mature adequately to support hemodialysis, as well as development of neointimal hyperplasia (NIH) that narrows the AVF lumen, typically near the fistula anastomosis. Failure due to NIH involves vascular cell activation and migration and extracellular matrix remodeling with complex interactions of growth factors, adhesion molecules, inflammatory mediators, and chemokines, all of which result in maladaptive remodeling. Different strategies have been proposed to prevent and treat AVF failure, based on current understanding of the modes and pathology of access failure; these approaches range from appropriate patient selection and use of alternative surgical strategies for fistula creation, to the use of novel interventional techniques or drugs to treat failing fistulae. Effective treatments to prevent or treat AVF failure requires a multidisciplinary approach involving nephrologists, vascular surgeons and interventional radiologists, allowing careful patient selection and the use of tailored systemic or localized interventions to improve patient-specific outcomes. This review provides contemporary information on the underlying mechanisms of AVF maturation and failure and discusses the broad spectrum of options that can be tailored for specific therapy.

We demonstrate in this report that solution X-ray scattering data can be utilized to precisely define the global structure and, therefore, implicitly the interfaces of an RNA:RNA complex. Defining the interfaces among components and the global structure of multicomponent systems is one of the essential problems in understanding biological interactions on a molecular level. However, identifying molecular interfaces is not an easy task for solution NMR spectroscopists. To resolve this problem, a widely used protocol is to prepare various sophisticated but labor-intensive and sometimes costly isotope-labeled samples and apply NMR isotope-filter experiments. 1-4 Moreover, global structures are often underdetermined, due to a general lack of experimentally measured NMRderived restraints that define the overall dimensionalities and shapes of biomacromolecules and complexes in solution, even if residual dipolar coupling has been utilized to provide global orientation restraints. 5 This lack is particularly severe in the structural determination of RNA molecules or complexes, where the proton spin density is much lower than that in protein counterparts, the structures generally tend to be elongated, and there are few options in selective-labeling sample preparation schemes. Furthermore, isotope filter/edited nuclear Overhauser effect (NOE) experiments are in general rather insensitive. Even when there are observable NOEs, assigning them is often challenging and time-consuming.Small-angle X-ray or neutron scattering (SAXS and SANS) data contain information about the overall shape and dimensionality of biomacromolecules in solution 6-8 and have recently been utilized directly to refine protein solution structures in combination with NMR restraints in order to achieve accurate global orders of singlechain multidomain proteins. 9,10 The utilization of SAXS data to define the global structure and consequently identify the interfaces of complexes of an RNA complex has not been reported. We report here a method that utilizes SAXS data to define the global structure and consequently to identify the interfaces of an RNA complex without intermolecular NOE distance restraints and to refine the global shape of the RNA complex. We demonstrate the utility of the method using a 30 kDa homodimeric tetraloop-receptor RNA complex, which is a commonly occurring RNA tertiary structural motif involved in helical packing. 11 The structure of the complex has been determined using heteronuclear solution NMR spectroscopy. 12,13 In the previous determination, the relative position and the orientation between the two subunits were restrained using 36 × 2 intermolecular NOE distance and hydrogen bond restraints together with 9 × 2 imino residual dipolar couplings (RDCs).For a given set of RDCs that are measured in one alignment medium, there are four satisfying discrete orientations for a subunit. In the case of a homodimer with a C 2 -axial symmetry, the orientations of the two subunits are related to each other within four possible choices. 14-16...

Metal ions are critical for the proper folding of RNA, and the GAAA tetraloop-receptor is necessary for the optimal folding and function of many RNAs. We have used NMR to investigate the role of metal ions in the structure of the tetraloop-receptor in solution. The NMR data indicate native tertiary structure is formed under a wide range of ionic conditions. The lack of conformational adaptation in response to very different ionic conditions argues against a structural role for divalent ions. Nuclear Overhauser effects to cobalt hexammine and paramagnetic relaxation enhancement induced by manganese ions were used to determine the NMR structures of the tetraloop receptor in association with metal ions, providing the first atomic-level view of these interactions in the solution state. Five manganese and two cobalt hexammine ions could be localized to the RNA surface. The locations of the associated metal ions are similar, but not identical to, those of previously determined crystal structures. The sites of association are in general agreement with nonlinear Poisson-Boltzmann calculations of the electrostatic surface, emphasizing the general importance of diffusely associated ions in RNA tertiary structure.