Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease

Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in podocytes. SV129 mice were subjected to 5/6-nephrectomy which resulted in arterial hypertension and albuminuria. Subgroups of animals were treated with the Rac-1 inhibitor EHT1846, the ROCK inhibitor SAR407899 and the ACE inhibitor Ramipril. Only Ramipril reduced hypertension. In contrast, all inhibitors markedly attenuated albumin excretion as well as glomerular and tubulo-interstitial damage. The combination of SAR407899 and Ramipril was more effective in preventing albuminuria than Ramipril alone. To study the involved mechanisms, podocytes were cultured from SV129 mice and exposed to static stretch in the Flexcell device. This activated RhoA and Rac-1 and led via TGFβ to apoptosis and a switch of the cells into a more mesenchymal phenotype, as evident from loss of WT-1 and nephrin and induction of α-SMA and fibronectin expression. Rac-1 and ROCK inhibition as well as blockade of TGFβ dramatically attenuated all these responses. This suggests that Rac-1 and RhoA are mediators of podocyte dysfunction in CKD. Inhibition of Rho-GTPases may be a novel approach for the treatment of CKD

In search of spring mires in Namibia:The Waterberg area revisited

The scarcity of peatlands and mires in Namibia is well known. Peatlands have been found in the north, which is the wettest part of the country. In the 1930s, spring mires were reported by German geologists in the Waterberg area, which also has relatively high annual precipitation. This short note reports some field observations and a literature search for old documents that mention the occurrence of springs and spring mires in the Waterberg region. The search was done by IMCG members who visited the Waterberg area in August 2014. We found springs, but no real mires. However, we found remnants of what might have been a large spring mire similar to that reported by the German geologist Paul Range, who found “local spring mires (Quellmoore) with a peat thickness of several metres in northern South-West Africa”. Whether or not our peat remnants were situated at the same site as the Range discovery could not be assessed. We compared the landscape position of the peat remnants and spring in the Waterberg area of Namibia with information from an ongoing ecohydrological study in the Waterberg area of Limpopo Province, South Africa

Production and characterization of miro- and nano-features in biomedical alumina and zirconia ceramics using a tape casting route

A process of micromolding, delivering micro- and nanopatterned ceramic surfaces for biomaterial applications is described in this work. To create the desired structures, tape casting of ceramic slurries on microfabricated silicon mold was used. Several tape casting slurry compositions were tested to evaluate the feasibility of transferring micro- and nano-features from silicon molds. Used ceramics were alumina (α-Al2O3) and yttria stabilized zirconia. Three types of polymeric binders for the green tape (PVB, PES, and PVP) were investigated using three different solvents (ethanol, n-methyl-pyrrolidone, water). Well-defined features in shapes of wells with diameters down to 2.4 μm and a depth of 10 μm and pillars with diameters down to 1.7 μm and a height of 3 μm were obtained. Morphology, grain size and porosity of the sintered bodies were characterized. Finally fibroblast cells were cultured on the surfaces in order to observe their morphology under influence of the microstructured surfaces

Adjoint formulation and constraint handling for gradient-based optimization of compositional reservoir flow

An adjoint formulation for the gradient-based optimization of oil-gas compositional reservoir simulation problems is presented. The method is implemented within an automatic differentiation-based compositional flow simulator (Stanford's Automatic Differentiation-based General Purpose Research Simulator, AD-GPRS). The development of adjoint procedures for general compositional problems is much more challenging than for oil-water problems due to the increased complexity of the code and the underlying physics. The treatment of nonlinear constraints, an example of which is a maximum gas rate specification in injection or production wells, when the control variables are well bottom-hole pressures, poses a particular challenge. Two approaches for handling these constraints are presented—a formal treatment within the optimizer and a simpler heuristic treatment in the forward model. The relationship between discrete and continuous adjoint formulations is also elucidated. Results for four example cases of increasing complexity are presented. Improvements in the objective function (cumulative oil produced) relative to reference solutions range from 4.2 to 11.6 %. The heuristic treatment of nonlinear constraints is shown to offer a cost-effective means for obtaining feasible solutions, which are, in some cases, better than those obtained using the formal constraint handling procedure

Hybridizing network reluctance and boundary integral methods: comparisons on an E-core actuator

International audienceHybridizing the network reluctance method (NRM) and the boundary integral method (BIM) aims to take advantage of both methods. First for ferromagnetic materials in order to take non linearity into account, and second for surrounding air in order to include fringing and leakages accurately. The automation of such modeling has been done with dedicated software and is compared to the tooth contour method (TCM) and finite element (FEM) simulations, which is applied to an E-core actuator

Human condensin function is essential for centromeric chromatin assembly and proper sister kinetochore orientation.

Condensins I and II in vertebrates are essential ATP-dependent complexes necessary for chromosome condensation in mitosis. Condensins depletion is known to perturb structure and function of centromeres, however the mechanism of this functional link remains elusive. Depletion of condensin activity is now shown to result in a significant loss of loading of CENP-A, the histone H3 variant found at active centromeres and the proposed epigenetic mark of centromere identity. Absence of condensins and/or CENP-A insufficiency produced a specific kinetochore defect, such that a functional mitotic checkpoint cannot prevent chromosome missegregation resulting from improper attachment of sister kinetochores to spindle microtubules. Spindle microtubule-dependent deformation of both inner kinetochores and the HEC1/Ndc80 microtubule-capturing module, then results in kinetochore separation from the Aurora B pool and ensuing reduced kinase activity at centromeres. Moreover, recovery from mitosis-inhibition by monastrol revealed a high incidence of merotelic attachment that was nearly identical with condensin depletion, Aurora B inactivation, or both, indicating that the Aurora B dysfunction is the key defect leading to chromosome missegregation in condensin-depleted cells. Thus, beyond a requirement for global chromosome condensation, condensins play a pivotal role in centromere assembly, proper spatial positioning of microtubule-capturing modules and positioning complexes of the inner centromere versus kinetochore plates

House mouse colonization patterns on the sub-Antarctic Kerguelen Archipelago suggest singular primary invasions and resilience against re-invasion

Starting from Western Europe, the house mouse (Mus musculus domesticus) has spread across the globe in historic times. However, most oceanic islands were colonized by mice only within the past 300 years. This makes them an excellent model for studying the evolutionary processes during early stages of new colonization. We have focused here on the Kerguelen Archipelago, located within the sub-Antarctic area and compare the patterns with samples from other Southern Ocean islands

In search of spring mires in Namibia:The Waterberg area revisited

The scarcity of peatlands and mires in Namibia is well known. Peatlands have been found in the north, which is the wettest part of the country. In the 1930s, spring mires were reported by German geologists in the Waterberg area, which also has relatively high annual precipitation. This short note reports some field observations and a literature search for old documents that mention the occurrence of springs and spring mires in the Waterberg region. The search was done by IMCG members who visited the Waterberg area in August 2014. We found springs, but no real mires. However, we found remnants of what might have been a large spring mire similar to that reported by the German geologist Paul Range, who found “local spring mires (Quellmoore) with a peat thickness of several metres in northern South-West Africa”. Whether or not our peat remnants were situated at the same site as the Range discovery could not be assessed. We compared the landscape position of the peat remnants and spring in the Waterberg area of Namibia with information from an ongoing ecohydrological study in the Waterberg area of Limpopo Province, South Africa