ACTIN: Structure and Function : Towards an understanding of the conformational states of actin monomer and filament

Actin is a major structural protein of the eukaryotic cytoskeleton and plays a crucial role in cell motility, adhesion, morphology and intracellular transport. Its biologically active form is the filament (F-actin), which is assembled from monomeric G-actin. In this thesis, the structural characteristics of both G- and F-actin are studied using molecular dynamics simulations. First, the crystallographically-determined 'open' and 'closed' conformational states of Gactin are characterized in aqueous solution, with either ATP or ADP bound in the nucleotide binding pocket. In both nucleotide states, the open state closes in the absence of the actin-binding protein profilin, suggesting that the open state is not a stable conformation of isolated G-actin. Further, the simulations reveal the existence of a structurally well-defined, compact, 'superclosed' state of ATP-G-actin, as yet unseen crystallographically and absent in the ADP-Gactin simulations. The superclosed state resembles structurally the actin monomer in filament models and we suggest it to be the polymerization competent conformation of G-actin. Furthermore, we introduce a new actin filament model, the Holmes-2010 model that incorporates the global structure of a recently published model but in addition conserves internal stereochemistry. The improved quality of the Holmes-2010 model is apparent in a comparison made with other recent F-actin models using molecular dynamics simulation, monitoring a number of structural determinants. In addition, simulations of the model are carried out in states with both ATP or ADP bound and local hydrogen-bonding differences characterized. The results point to the significance of a direct interaction of GLN137 with ATP for activation of ATPase activity after the G-to-F-actin transition. The findings presented here may thus be a step towards a better understanding of the nucleotide-dependent structural differences of actin that lead to its functional differences

Correlation of lumbar lateral recess stenosis in magnetic resonance imaging and clinical symptoms

Aim: To assess the correlation of lateral recess stenosis (LRS) of lumbar segments L4/5 and L5/S1 and the Oswestry Disability Index (ODI). Methods: Nine hundred and twenty-seven patients with history of low back pain were included in this uncontrolled study. On magnetic resonance images (MRI) the lateral recesses (LR) at lumbar levels L4/5 and L5/S1 were evaluated and each nerve root was classified into a 4-point grading scale (Grade 0-3) as normal, not deviated, deviated or compressed. Patient symptoms and disability were assessed using ODI. The Spearman’s rank correlation coefficient was used for statistical analysis (P < 0.05). Results: Approximately half of the LR revealed stenosis (grade 1-3; 52% at level L4/5 and 42% at level L5/S1) with 2.2% and 1.9% respectively reveal a nerve root compression. The ODI score ranged from 0%-91.11% with an arithmetic mean of 34.06% ± 16.89%. We observed a very weak statistically significant positive correlation between ODI and LRS at lumbar levels L4/5 and L5/S1, each bilaterally (L4/5 left: rho < 0.105, P < 0.01; L4/5 right: rho < 0.111, P < 0.01; L5/S1 left: rho 0.128, P < 0.01; L5/S1 right: rho < 0.157, P < 0.001). Conclusion: Although MRI is the standard imaging tool for diagnosing lumbar spinal stenosis, this study showed only a weak correlation of LRS on MRI and clinical findings. This can be attributed to a number of reasons outlined in this study, underlining that imaging findings alone are not sufficient to establish a reliable diagnosis for patients with LRS

Effect of Higher Harmonic Control on Helicopter Rotor Blade-Vortex Interaction Noise: Prediction and Initial Validation

The paper presents a status of theoretical tools of AFDD, DLR, NASA and ONERA for prediction of the effect of HHC on helicopter main rotor BVI noise. Aeroacoustic predictions from the four research centers, concerning a wind tunnel simulation of a typical descent flight case without and with HHC are presented and compared. The results include blade deformation, geometry of interacting vortices, sectional loads and noise. Acoustic predictions are compared to experimental data. An analysis of the results provides a first insight of the mechanisms by which HHC may affect BVI noise