A combinatorial approach of Proteomics and Systems Biology in unravelling the mechanisms of acute kidney injury (AKI): involvement of NMDA receptor GRIN1 in murine AKI

BACKGROUND: Acute kidney injury (AKI) is a frequent condition in hospitalised patients undergoing major surgery or the critically ill and is associated with increased mortality. Based on the volume of the published literature addressing this condition, reporting both supporting as well as conflicting molecular evidence, it is apparent that a comprehensive analysis strategy is required to understand and fully delineate molecular events and pathways which can be used to describe disease induction and progression as well as lead to a more targeted approach in intervention therapies.<p></p> RESULTS: We used a Systems Biology approach coupled with a de-novo high-resolution proteomic analysis of kidney cortex samples from a mouse model of folic acid-induced AKI (12 animals in total) and show comprehensive mapping of signalling cascades, gene activation events and metabolite interference by mapping high-resolution proteomic datasets onto a de-novo hypothesis-free dataspace. The findings support the involvement of the glutamatergic signalling system in AKI, induced by over-activation of the N-methyl-D-aspartate (NMDA)-receptor leading to apoptosis and necrosis by Ca2+-influx, calpain and caspase activation, and co-occurring reactive oxygen species (ROS) production to DNA fragmentation and NAD-rundown. The specific over-activation of the NMDA receptor may be triggered by the p53-induced protein kinase Dapk1, which is a known non-reversible cell death inducer in a neurological context. The pathway mapping is consistent with the involvement of the Renin-Angiotensin Aldosterone System (RAAS), corticoid and TNFalpha signalling, leading to ROS production and gene activation through NFkappaB, PPARgamma, SMAD and HIF1alpha trans-activation, as well as p53 signalling cascade activation. Key elements of the RAAS-glutamatergic axis were assembled as a novel hypothetical pathway and validated by immunohistochemistry.<p></p> CONCLUSIONS: This study shows to our knowledge for the first time in a molecular signal transduction pathway map how AKI is induced, progresses through specific signalling cascades that may lead to end-effects such as apoptosis and necrosis by uncoupling of the NMDA receptor. Our results can potentially pave the way for a targeted pharmacological intervention in disease progression or induction.<p></p&gt

Temperature dependence of surface stress across an order-disorder transition: p(1x2)O/W(110)

Strain relaxations of a p(1x2) ordered oxygen layer on W(110) are measured as a function of temperature across the disordering transition using low-energy electron diffraction. The measured strains approach values of 0.027 in the [1-10] and -0.053 in the [001] direction. On the basis of the measured strain relaxations, we give quantitative information on temperature-dependent surface stress using the results of ab initio calculations. From the surface formation energy for different strains, determined by first-principles calculations, we estimate that surface stress changes from -1.1 for the ordered phase to -0.2N/m for the disordered one along [1-10], and from 5.1 to 3.4 N/m along [001]. Moreover, our observation that the strains scale inversely with domain size confirms that the strain relaxation takes place at the domain boundaries.Comment: 8 pages, 5 figure

Strain relaxation in small adsorbate islands: O on W(110)

The stress-induced lattice changes in a p(1x2) ordered oxygen layer on W(110) are measured by low-energy electron diffraction. We have observed that small oxygen islands show a mismatch with the underlying lattice. Our results indicate that along [1-10] the average mismatch scales inversely with the island size as 1/L for all oxygen coverages up to 0.5 ML, while along [001] it is significant only for the smallest oxygen islands and scales as a higher power of the inverse island size. The behaviour along [1-10] is described by a one-dimensional finite-size Frenkel-Kontorova model. Using this model, together with calculated force constants, we make a quantitative estimate for the change of surface-stress upon oxygen adsorption. The result is consistent with our ab-initio calculations, which give a relative compressive stress of -4.72 N/m along [1-10] and a minute relative tensile stress of 0.15 N/m along [001]. The scaling along [001] is qualitatively explained as an effect induced by the lattice relaxation in the [1-10] direction.Comment: 22 pages, 5 figure

Element specific characterization of heterogeneous magnetism in (Ga,Fe)N films

We employ x-ray spectroscopy to characterize the distribution and magnetism of particular alloy constituents in (Ga,Fe)N films grown by metal organic vapor phase epitaxy. Furthermore, photoelectron microscopy gives direct evidence for the aggregation of Fe ions, leading to the formation of Fe-rich nanoregions adjacent to the samples surface. A sizable x-ray magnetic circular dichroism (XMCD) signal at the Fe L-edges in remanence and at moderate magnetic fields at 300 K links the high temperature ferromagnetism with the Fe(3d) states. The XMCD response at the N K-edge highlights that the N(2p) states carry considerable spin polarization. We conclude that FeN{\delta} nanocrystals, with \delta > 0.25, stabilize the ferromagnetic response of the films.Comment: 4 pages, 3 figures, 1 tabl

Stress engineering at the nanometer scale: Two-component adlayer stripes

Spontaneously formed equilibrium nanopatterns with long-range order are widely observed in a variety of systems, but their pronounced temperature dependence remains an impediment to maintain such patterns away from the temperature of formation. Here, we report on a highly ordered stress-induced stripe pattern in a two-component, Pd-O, adsorbate monolayer on W(110), produced at high temperature and identically preserved at lower temperatures. The pattern shows a tunable period (down to 16 nm) and orientation, as predicted by a continuum model theory along with the surface stress and its anisotropy found in our DFT calculations. The control over thermal fluctuations in the stripe formation process is based on the breaking/restoring of ergodicity in a high-density lattice gas with long-range interactions upon turning off/on particle exchange with a heat bath.Comment: 6 pages, 4 figure

Electrostatic internal energy using the method of images

For several configurations of charges in the presence of conductors, the method of images permits us to obtain some observables associated with such a configuration by replacing the conductors with some image charges. However, simple inspection shows that the potential energy associated with both systems does not coincide. Nevertheless, it can be shown that for a system of a grounded or neutral conductor and a distribution of charges outside, the external potential energy associated with the real charge distribution embedded in the field generated by the set of image charges is twice the value of the internal potential energy associated with the original system. This assertion is valid for any size and shape of the conductor, and regardless of the configuration of images required. In addition, even in the case in which the conductor is not grounded nor neutral, it is still possible to calculate the internal potential energy of the original configuration through the method of images. These results show that the method of images could also be useful for calculations of the internal potential energy of the original system.Comment: 5 pages, 3 figures. New discussions added. Minor change

phase coexistence in two dimensional fe 0 70 ni 0 30 films on w 110

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Combination of DROOL rules and Protégé knowledge bases in the ONTO-H annotation tool

ONTO-H is a semi-automatic collaborative tool for the semantic annotation of documents, built as a Protégé 3.0 tab plug-in. Among its multiple functionalities aimed at easing the document annotation process, ONTO-H uses a rule-based system to create cascading annotations out from a single drag and drop operation from a part of a document into an already existing concept or instance of the domain ontology being used for annotation. It also gives support to the detection of name conflicts and instance duplications in the creation of the annotations. The rule system runs on top of the open source rule engine DROOLS and is connected to the domain ontology used for annotation by means of an ad-hoc programmed Java proxy

Domain-wall depinning assisted by pure spin currents

We study the depinning of domain walls by pure diffusive spin currents in a nonlocal spin valve structure based on two ferromagnetic permalloy elements with copper as the nonmagnetic spin conduit. The injected spin current is absorbed by the second permalloy structure with a domain wall and from the dependence of the wall depinning field on the spin current density we find an efficiency of 6*10^{-14}T/(A/m^2), which is more than an order of magnitude larger than for conventional current induced domain wall motion. Theoretically we reproduce this high efficiency, which arises from the surface torques exerted by the absorbed spin current that lead to efficient depinning.Comment: 11 pages, 3 figures, accepted for publication in Phys. Rev. Let