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C-reactive protein (CRP) is an early-stage acute phase protein and highly upregulated in response to inflammatory reactions. We recently identified a novel mechanism that leads to a conformational change from the native, functionally relatively inert, pentameric CRP (pCRP) structure to a pentameric CRP intermediate (pCRP*) and ultimately to the monomeric CRP (mCRP) form, both exhibiting highly pro-inflammatory effects. This transition in the inflammatory profile of CRP is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine lipid head groups. We designed a tool compound as a low molecular weight CRP inhibitor using the structure of phosphocholine as a template. X-ray crystallography revealed specific binding to the phosphocholine binding pockets of pCRP. We provide in vitro and in vivo proof-of-concept data demonstrating that the low molecular weight tool compound inhibits CRP-driven exacerbation of local inflammatory responses, while potentially preserving pathogen-defense functions of CRP. The inhibition of the conformational change generating pro-inflammatory CRP isoforms via phosphocholine-mimicking compounds represents a promising, potentially broadly applicable anti-inflammatory therapy.

Phagocytosis and the formation of reactive oxygen species (ROS) in phagocytic leukocytes are an effective killing mechanism of the innate host defense. These cellular processes of innate immunity function in a complex interplay with humoral factors. C-reactive protein (CRP) in its activated, monomeric isoform (mCRP) has been shown to activate immune cells via the classical complement pathway. We investigated the complement-dependent effects of monomeric CRP (mCRP) on neutrophils and monocyte subtypes using complement-specific inhibitors by both flow cytometry and confocal fluorescence microscopy. We demonstrate that CRP-induced ROS generation is a conformation-specific and complement-dependent process in leukocyte subsets with classical monocytes as the primary source of ROS amongst human monocyte subsets. Elucidation of this complex interplay of CRP and complement in inflammation pathophysiology might help to improve anti-inflammatory therapeutic strategies.

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Four different numerical approaches are compared for the rise of liquid between two parallel plates. These are an Arbitrary Lagrangian-Eulerian method (OpenFOAM solver interTrackFoam), a geometric volume of fluid code (FS3D), an algebraic volume of fluid method (OpenFOAM solver interFoam), and a level set approach (BoSSS). The first three approaches discretize the bulk equation using a finite volume method while the last one employs an extended discontinuous Galerkin discretization. The results are compared to ODE models which are the classical rise model and an extended model that incorporates a Navier slip boundary condition on the capillary walls and levels at a corrected stationary rise height. All physical parameters are based on common requirements for the initial conditions, short simulation time, and a non-dimensional parameter study. The comparison shows excellent agreement between the different implementations with minor quantitative deviations for the adapted interFoam implementation. While the qualitative agreement between the full solutions of the continuum mechanical approach and the reference model is good, the quantitative comparison is only reasonable, especially for cases with increasing oscillations. Furthermore, reducing the slip length changes the solution qualitatively as oscillations are completely damped in contrast to the solution of the ODE models. To provide reference data for a full continuum simulation of the capillary rise problem, all results are made available online., Comment: 38 pages, 17 figures, benchmark data available online

14 mei 2016, Contains fulltext : 184264.pdf (publisher's version ) (Closed access)

14 mei 2016, Contains fulltext : 184264.pdf (publisher's version ) (Closed access)

The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms. The molecular basis of this striking difference in the response to filovirus infections is not well understood. We report a systematic overview of differentially expressed genes, activity motifs and pathways in human and bat cells infected with the Ebola and Marburg viruses, and we demonstrate that the replication of filoviruses is more rapid in human cells than in bat cells. We also found that the most strongly regulated genes upon filovirus infection are chemokine ligands and transcription factors. We observed a strong induction of the JAK/STAT pathway, of several genes encoding inhibitors of MAP kinases (DUSP genes) and of PPP1R15A, which is involved in ER stress-induced cell death. We used comparative transcriptomics to provide a data resource that can be used to identify cellular responses that might allow bats to survive filovirus infections.

Recent experiments probing the conduction band electronic states in self-assembled dots, double dots and ring-like structures are reviewed. The results are discussed in view of contributions from quantization, magnetic forces and Coulomb interaction.

An investigation of the collateral damage produced by tactical nuclear weapons was conducted under Defense Nuclear Agency Contract No. DNA 001- 76-C-0039. The analysis of civilian casualties produced by prompt weapon effects (i.e., initial nuclear radiation, direct and indirect airblast effects and thermal radiation effects) was emphasized during that effort. During the early stages of that contract, an effort was devoted to identifying potential casualty-producing mechanisms which might extend to ranges farther than the prompt effects mentioned above. Fires produced by thermal radiation was one of the mechanisms identified. An effort was initiated in August of 1976 to scope the impact on collateral damage of fires produced by tactical nuclear weapons and the relationship between fires in residential areas and the resulting casualties. The effort included primary fires (those started by the thermal pulse), secondary fires (those started by secondary effects such as airblast, debris, etc.) and spread fires. This report summarizes the results of this effort, which was primarily conducted at the Stanford Research Institute by Stanley B. Martin and Steven J. Wiersma. It should be recognized that this was a preliminary scoping effort, intended more to identify any needs for further research than to provide definitive results for a wide range of burst scenarios.

Two basic problems inherent in the stratospheric application f all automatic frost-point hygrometers are examined. In particular, instrument inadequacy due to low rates of mass transfer is found to be a highly probable explanation of the current controversy about upperatmosphere water-vapor content. The second problem is that of contamination of the moist-air sample by water vapor desorbed from the instrument package and vehicle. The magnitude of this effect precludes a simple accommodation of low mass transfer rates by use of long sampling times. Measures to increase the reliability of future stratospheric data are recommended. (Author), See also Volume 1, AD-608 498.