Swedish Defence Research Agency

About: Swedish Defence Research Agency is a government organization based out in Stockholm, Sweden. It is known for research contribution in the topics: Radar & Laser. The organization has 1413 authors who have published 2731 publications receiving 56083 citations. The organization is also known as: Totalförsvarets forskningsinstitut.

Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling.

Abstract: Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia) to treat cholinergic deficiencies (e.g. in Alzheimer's disease), but may also act as dangerous toxins (e.g. nerve agents such as sarin). Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS). Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685•mAChE) is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical characterization, crystallography and computational chemistry provide a route to novel AChE inhibitors and reactivators.

Vitamin E down-modulates mitogen-activated protein kinases, nuclear factor-kappaB and inflammatory responses in lung epithelial cells.

Abstract: The airway epithelium plays an active role in acute lung inflammation by producing chemotactic factors and by expressing cell adhesion molecules involved in the migration of leucocytes to extravascular spaces. We have reported previously that neutrophil migration to airways can be down-modulated by exogenously administered vitamin E (alpha-tocopherol). The mechanism for this effect is not well understood, however. The action of alpha-tocopherol was investigated in human alveolar type II and bronchial epithelial cells stimulated with tumour necrosis factor-alpha. Treatment of alveolar epithelial cells with alpha-tocopherol resulted in down-regulated cell surface expression of intercellular adhesion molecule-1 (ICAM-1). On bronchial epithelial cells, both ICAM-1 and vascular adhesion molecule-1 were decreased, leading to diminished adherence of leucocytes to the cells. The production of the neutrophil chemoattractant interleukin-8 was attenuated in both alveolar and bronchial cells. These effects were preceded by reduced activation of the mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinase (ERK1/2) and p38, as well as down-regulation of nuclear factor-kappaB. Comparing the effects of alpha-tocopherol with that of specific inhibitors of MAPK and protein kinase C (PKC) revealed that effects appear to be partly independent of PKC inhibition. These results implicate the anti-inflammatory action of alpha-tocopherol in addition to its anti-oxidant properties.

Susceptibility of Civilian GPS Receivers to Electromagnetic Radiation

Abstract: Civilian handheld global positioning system receivers were tested for their susceptibility against radiated electromagnetic disturbances of different characteristics and field levels. This susceptibility data were compared to the existing electromagnetic compatibility (EMC) immunity requirements for electronic devices. Some of the receivers were disrupted by continues waves at in- as well as out-of-band frequencies, at field levels far below the existing EMC requirements. The possible reason for this is discussed. In general, due to the ever-growing use of commercial-off-the-shelf equipment even for critical functions, certificates of conformity to current EMC requirements may be inadequate.