Slx5/Slx8-dependent ubiquitin hotspots on chromatin contribute to stress tolerance

Chromatin is a highly regulated environment, and protein association with chromatin is often controlled by post-translational modifications and the corresponding enzymatic machinery. Specifically, SUMO-targeted ubiquitin ligases (STUbLs) have emerged as key players in nuclear quality control, genome maintenance, and transcription. However, how STUbLs select specific substrates among myriads of SUMOylated proteins on chromatin remains unclear. Here, we reveal a remarkable co-localization of the budding yeast STUbL Slx5/Slx8 and ubiquitin at seven genomic loci that we term "ubiquitin hotspots". Ubiquitylation at these sites depends on Slx5/Slx8 and protein turnover on the Cdc48 segregase. We identify the transcription factor-like Ymr111c/Euc1 to associate with these sites and to be a critical determinant of ubiquitylation. Euc1 specifically targets Slx5/Slx8 to ubiquitin hotspots via bipartite binding of Slx5 that involves the Slx5 SUMO-interacting motifs and an additional, novel substrate recognition domain. Interestingly, the Euc1-ubiquitin hotspot pathway acts redundantly with chromatin modifiers of the H2A.Z and Rpd3L pathways in specific stress responses. Thus, our data suggest that STUbL-dependent ubiquitin hotspots shape chromatin during stress adaptation

Small viscosity behavior of a homogeneous, quasi-geostrophic, ocean circulation mode

Insensitivity to turbulent closure in the wind-driven nonlinear Stommel-Munk model is addressed theoretically and numerically. The QG energy equation is used to show that, with the assumption that the maximum velocities occur at inertial length scales or smaller, a Sverdrup interior is consistent with the small Rossby number assumption only when the frictional parameters exceed critical values. For frictional parameters smaller than these values, valid solutions must decrease the energy source. This is possible for non-Sverdrup solutions since the energy source is dependent on the solution. The steady-state behavior of the model was investigated via a pseudo-arclength continuation algorithm. Dependence on the boundary layer Reynolds number, Re, was investigated by varying the eddy viscosity for fixed wind forcing. A tendency to decrease the energy source was found for solutions that are nonsymmetric about the center latitude. Antisymmetric solutions displayed the opposite behavior and diverged more quickly with increasing Re. The robustness of the results to dynamic boundary condition, symmetry and strength of wind stress, time dependence and bottom friction were tested. Some aspects of the nonsymmetric solutions appeared insensitive to Re

Effects of large-scale topography on abyssal circulation

Two models are employed to study the effect of topographically induced planetary islands (i.e. closed contours of potential vorticity) on the abyssal circulation of an ocean basin. The first is a steady state calculation using a 1½ layer model of the abyssal ocean forced by a uniform upwelling. Planetary geostrophic dynamics yield a characteristic equation in which the inverse potential vorticity serves as a streamfunction for the characteristic velocity field. Aside from warping the classic Stommel-Arons flow in the immediate vicinity of the planetary island, the topography introduces two new elements to the zonal flow west of the topography. The first of these is a system of two zonal jets, flowing in opposite directions and centered on the separatrix contour. The second is an acceleration (or retardation) of the zonal flow (with respect to the classic flat-bottom result) in a broader region of the basin. The strengths of both the double jets and the broader regions of enhanced/retarded zonal flow are found to be determined by forcing in relatively small areas of the basin. The former are excited in the vicinity of saddle points of potential vorticity whereas the latter are excited primarily where the curvature of potential vorticity contours is large. The second model, a time dependent 2½ layer planetary geostrophic model is then used to investigate the spin-up problem. The model is forced by a uniform upwelling through each of the two interfaces. The density jump at the upper interface (e.g. the thermocline) is chosen to be ten times that at the lower interface, a disparity which leads to a separation in time scale between the fast and the slow waves of the system. Topography, however, induces a strong coupling between these two modes and results in a quick baroclinization of the flow over the topography. This baroclinization occurs well before the arrival of the nondispersive wave front from the eastern boundary and thus differs from the traditional view of spin-up

Pinning forces of sliding drops at defects

Wetting of surfaces depends critically on defects which alter the shape of the drop. However, no experimental verification of forces owing to the three phase contact line deformation at single defects is available. We imaged the contact line of sliding drops on hydrophobic surfaces by video microscopy. From the deformation of the contact line, we calculate the force acting on a sliding drop using an equation going back to Joanny and de Gennes (J. Chem. Phys., 81 (1984) 554). The calculated forces quantitatively agree with directly measured forces acting between model defects and water drops. In addition, both forces quantitatively match with the force calculated by contact angle differences between the defect and the surface. The quantitative agreement even holds for defects reaching a size of $40\%$ of the drop diameter. Our validation for drop’s pinning forces at single defects is an important step towards a general understanding of contact line motion on heterogeneous surfaces

Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9

OBJECTIVE: The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin-Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle-Eye-Brain Disease and Walker-Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP-related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities. METHODS: Registration is patient-initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain. RESULTS: Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C \u3e A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C \u3e A compared with individuals heterozygous for c.826C \u3e A. This divergence was replicated in ages of loss of running ability, wheelchair-dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C \u3e A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129). INTERPRETATION: The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial-ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies

DNS of Turbulent Heat Transfer in Impinging Jets at Different Reynolds and Prandtl Numbers

The heat transfer between an impinging circular jet and a flat plate is studied by means of direct numerical simulations (DNS) for different Prandtl numbers of the fluid. The thermal field is resolved for Pr= 1, 0.72, 0.025, and 0.01. The flow is incompressible and the temperature is treated as a passive scalar field. The jet originates from a fully developed turbulent pipe flow and impinges perpendicularly on a smooth solid heated plate placed at two pipe diameters distance from the jet exit section. The values of Reynolds numbers based on the pipe diameter and bulk mean velocity in the pipe are set to Re= 5300 and Re= 10000. Inflow boundary conditions are enforced using a precursor simulation. Heat transfer at the wall is addressed through the Nusselt number distribution and main flow field statistics. At fixed Reynolds number it is shown that the Prandtl number influences the intensity of the Nusselt number at a given radial location, and that the Nusselt number distribution along the plate exhibit similar features at different Prandtl numbers. The characteristic secondary peak in the Nusselt number distribution is found for both Reynolds numbers for Pr= 0.025 and Pr = 0.01. All the simulations presented in this study were performed with the high order spectral element code Nek5000. Generated flow field statistics are available in the open access repository KITOpen

Anti-phospholipid-antibodies in patients with relapsing polychondritis

Relapsing polychondritis (RP) is an extremly rare multisystemic disease thought to be of autoimmune origin. In order to assess if RP is associated with anti-phospholipid antibodies (aPL), clinical data and sera of 21 patients with RP were collected in a multicentre study. Concentration of anti-cardiolipin antibodies (aCL) (IgG-, IgM-and IgA-isotypes), anti-phosphatidylserine-antibodies (aPS) (IgG-and IgM-isotypes) and anti-β-2-glycoprotein I-antibodies (aβ2 GPI) were measured by ELISA. In eight patients aCL were found to be elevated. One patient had elevated aPS. No patient had elevated aβ2 GPI. No patient had clinical signs and symptoms of a aPL syndrome. Interestingly, the two RP patients with the highest aPL had concomitant systemic lupus erythematosus (SLE). Therefore the presence of elevated aPL in RP is probably more closely related to an associated SLE than to RP itself. There is no convincing evidence that aPL are associated with RP