Preoperative plasma growth-differentiation factor-15 for prediction of acute kidney injury in patients undergoing cardiac surgery

Covariate plot of the predictions from the random forest model. Four variables are displayed. Within each box, the x-axis denotes plasma creatinine (Îźmol/l), the y-axis the probability of developing cardiac-surgery-associated acute kidney injury (CSA-AKI). Within each column of plots, the additive Euroscore increases from bottom to top (legend, right). Within each row of plots the growth-differentiation factor-15 (GDF-15) levels increase from left to right. Significant non-linear interaction takes place between GDF-15 and creatinine. Within each additive Euroscore category (row of plots), increases in GDF-15 (plots more to the right within each row) increase the probability of developing CSA-AKI. However, this effect is more prominent in patients with normal creatinine (x-axis label of each plot). (TIFF 3197 kb

Molecular Determinants of Synaptic Function Gephyrin: does splicing affect its function?

Abstract Gephyrin is a protein involved in both synaptic anchoring of inhibitory ligand-gated ion channels and molybdenum cofactor synthesis. Substantial progress has been made in understanding its gene and protein structures. Furthermore, numerous binding partners of gephyrin have been identified. The mechanisms by which these interactions occur are unclear at present. Alternative splicing has been proposed to contribute to gephyrin's functional diversity within single cells as well as in different cell types and tissues

Forty years of carabid beetle research in Europe - from taxonomy, biology, ecology and population studies to bioindication, habitat assessment and conservation

Volume: 100Start Page: 55End Page: 14

Dissecting spin-phonon equilibration in ferrimagnetic insulators by ultrafast lattice excitation

To gain control over magnetic order on ultrafast time scales, a fundamental understanding of the way electron spins interact with the surrounding crystal lattice is required. However, measurement and analysis even of basic collective processes such as spin-phonon equilibration have remained challenging. Here, we directly probe the flow of energy and angular momentum in the model insulating ferrimagnet yttrium iron garnet. After ultrafast resonant lattice excitation, we observe that magnetic order reduces on distinct time scales of 1 ps and 100 ns. Temperature-dependent measurements, a spin-coupling analysis, and simulations show that the two dynamics directly reflect two stages of spin-lattice equilibration. On the 1-ps scale, spins and phonons reach quasi-equilibrium in terms of energy through phonon-induced modulation of the exchange interaction. This mechanism leads to identical demagnetization of the ferrimagnet’s two spin sublattices and to a ferrimagnetic state of increased temperature yet unchanged total magnetization. Finally, on the much slower, 100-ns scale, the excess of spin angular momentum is released to the crystal lattice, resulting in full equilibrium. Our findings are relevant for all insulating ferrimagnets and indicate that spin manipulation by phonons, including the spin Seebeck effect, can be extended to antiferromagnets and into the terahertz frequency range

Spatial Segregation of BMP/Smad Signaling Affects Osteoblast Differentiation in C2C12 Cells

BACKGROUND: Bone morphogenetic proteins (BMPs) are involved in a plethora of cellular processes in embryonic development and adult tissue homeostasis. Signaling specificity is achieved by dynamic processes involving BMP receptor oligomerization and endocytosis. This allows for spatiotemporal control of Smad dependent and non-Smad pathways. In this study, we investigate the spatiotemporal regulation within the BMP-induced Smad transcriptional pathway. METHODOLOGY/PRINCIPAL FINDINGS: Here we discriminate between Smad signaling events that are dynamin-dependent (i.e., require an intact endocytic pathway) and dynamin-independent. Inhibition of dynamin-dependent endocytosis in fluorescence microscopy and fractionation studies revealed a delay in Smad1/5/8 phosphorylation and nuclear translocation after BMP-2 stimulation of C2C12 cells. Using whole genome microarray and qPCR analysis, we identified two classes of BMP-2 induced genes that are differentially affected by inhibition of endocytosis. Thus, BMP-2 induced gene expression of Id1, Id3, Dlx2 and Hey1 is endocytosis-dependent, whereas BMP-2 induced expression of Id2, Dlx3, Zbtb2 and Krt16 is endocytosis-independent. Furthermore, we demonstrate that short term inhibition of endocytosis interferes with osteoblast differentiation as measured by alkaline phosphatase (ALP) production and qPCR analysis of osteoblast marker gene expression. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that dynamin-dependent endocytosis is crucial for the concise spatial activation of the BMP-2 induced signaling cascade. Inhibition of endocytic processes during BMP-2 stimulation leads to altered Smad1/5/8 signaling kinetics and results in differential target gene expression. We show that interfering with the BMP-2 induced transcriptional network by endocytosis inhibition results in an attenuation of osteoblast differentiation. This implies that selective sensitivity of gene expression to endocytosis provides an additional mechanism for the cell to respond to BMP in a context specific manner. Moreover, we suggest a novel Smad dependent signal cascade induced by BMP-2, which does not require endocytosis

Quantifying the Effects of Elastic Collisions and Non-Covalent Binding on Glutamate Receptor Trafficking in the Post-Synaptic Density

One mechanism of information storage in neurons is believed to be determined by the strength of synaptic contacts. The strength of an excitatory synapse is partially due to the concentration of a particular type of ionotropic glutamate receptor (AMPAR) in the post-synaptic density (PSD). AMPAR concentration in the PSD has to be plastic, to allow the storage of new memories; but it also has to be stable to preserve important information. Although much is known about the molecular identity of synapses, the biophysical mechanisms by which AMPAR can enter, leave and remain in the synapse are unclear. We used Monte Carlo simulations to determine the influence of PSD structure and activity in maintaining homeostatic concentrations of AMPARs in the synapse. We found that, the high concentration and excluded volume caused by PSD molecules result in molecular crowding. Diffusion of AMPAR in the PSD under such conditions is anomalous. Anomalous diffusion of AMPAR results in retention of these receptors inside the PSD for periods ranging from minutes to several hours in the absence of strong binding of receptors to PSD molecules. Trapping of receptors in the PSD by crowding effects was very sensitive to the concentration of PSD molecules, showing a switch-like behavior for retention of receptors. Non-covalent binding of AMPAR to anchored PSD molecules allowed the synapse to become well-mixed, resulting in normal diffusion of AMPAR. Binding also allowed the exchange of receptors in and out of the PSD. We propose that molecular crowding is an important biophysical mechanism to maintain homeostatic synaptic concentrations of AMPARs in the PSD without the need of energetically expensive biochemical reactions. In this context, binding of AMPAR with PSD molecules could collaborate with crowding to maintain synaptic homeostasis but could also allow synaptic plasticity by increasing the exchange of these receptors with the surrounding extra-synaptic membrane

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369