Folding and aggregation studies in the acylphosphatase-like family

Folding and misfolding of proteins are considered two sides of the same coin. The delicate equilibrium existing between these two processes is crucial for any living organism and its alterations can lead to the onset of several tremendous diseases, such as Alzheimer's and Parkinson's disease. The attainment of a profound knowledge of folding/misfolding processes is a key step to understand how life works and for discovering new therapies to these diseases. In this work the author shows that proteins can display enzymatic activity even in the absence of a compact three-dimensional structure, with important implications for the study of protein enzymes. Furthermore, the author investigates the formation of protein aggregates similar to those observed in patients of amyloid-related diseases

Predictive Control for Linear and Hybrid Systems

Model Predictive Control (MPC), the dominant advanced control approach in industry over the past twenty-five years, is presented comprehensively in this unique book. With a simple, unified approach, and with attention to real-time implementation, it covers predictive control theory including the stability, feasibility, and robustness of MPC controllers. The theory of explicit MPC, where the nonlinear optimal feedback controller can be calculated efficiently, is presented in the context of linear systems with linear constraints, switched linear systems, and, more generally, linear hybrid systems. Drawing upon years of practical experience and using numerous examples and illustrative applications, the authors discuss the techniques required to design predictive control laws, including algorithms for polyhedral manipulations, mathematical and multiparametric programming and how to validate the theoretical properties and to implement predictive control policies. The most important algorithms feature in an accompanying free online MATLAB toolbox, which allows easy access to sample solutions. Predictive Control for Linear and Hybrid Systems is an ideal reference for graduate, postgraduate and advanced control practitioners interested in theory and/or implementation aspects of predictive control

Folding and aggregation studies in the acylphosphatase-like family

Folding and misfolding of proteins are considered two sides of the same coin. The delicate equilibrium existing between these two processes is crucial for any living organism and its alterations can lead to the onset of several tremendous diseases, such as Alzheimer's and Parkinson's disease. The attainment of a profound knowledge of folding/misfolding processes is a key step to understand how life works and for discovering new therapies to these diseases. In this work the author shows that proteins can display enzymatic activity even in the absence of a compact three-dimensional structure, with important implications for the study of protein enzymes. Furthermore, the author investigates the formation of protein aggregates similar to those observed in patients of amyloid-related diseases

Automatic Identification of EUV structures on the Sun with a Fuzzy Clustering Algorithm

This technical report describes the first implementation of a Fuzzy c-means (FCM) algorithm for the automatic identification of structures on the Sun based on EUV images and photospheric magnetograms. Before the application of FCM, the AIA 193 Å images and HMI LOS magnetograms acquired by SDO have been pre-processed, and a geometrical approach to correct the limb brightening of EUV images is applied. Then, the images and the magnetograms are analyzed pixel-by-pixel by determining the degree of membership of each pixel to one of clusters, previously defined based on the analysis of a sample training dataset. The routines are written in IDL programming language and will be inserted in the SWELTO pipeline. The work described here was the subject of a Degree Thesis in Physics

Comprehensive Sun-to-Earth analysis of the Geoeffective Solar event of June 21, 2015: Effects on the Magnetosphere - Plasmasphere - Ionosphere system

A full-halo coronal mass ejection left the sun on June 21, 2015 from the active region NOAA 12371 encountering Earth on June 22, 2015, generating a G3 strong geomagnetic storm. The CME was associated with an M2 class flare observed at 01:42 UT, located near the center disk (N12E16). Using satellite data from solar, heliospheric, magnetospheric missions and ground-based instruments, we performed a comprehensive Sun-to-Earth analysis. In particular, we analyzed the active region evolution using ground-based and satellite instruments (BBSO, IRIS, HINODE, SDO/AIA, RHESSI -- Halpha, EUV, UV, X), the AR magnetograms, using data from SDO HMI, the relative particle data, using PAMELA instruments and the effects of interplanetary perturbation on cosmic ray intensity. We also evaluated the 1-8 $\AA$ soft X-ray and low-frequenct ($\sim$ 1 MHz) Type III radio burst time-integrated intensity (or fluence) of the flare in order to make a prediction of the associated Solar Energetic Particle (SEP) event by using the model developed by \cite{Laurenza09}. Inaddition, using ground based observations from lower to higher latitudes (INTERMAGNET - EMMA, etc.), we reconstructed the ionospheric current system associated to the geomagnetic Sudden Commencement. Furthermore, SuperDARN measurements are used to image the global ionospheric polar convection during the SSC and during the principal phases of the geomagnetic storm. Moreover, we investigated the dynamics of the plasmasphere during the different phases of the geomagnetic storm by examining the time evolution of the radial profiles of the equatorial plasma mass density derived from field line resonances detected at the EMMA network (1.5 $<$ L $<$ 6.5). Finally, we presented the general features of the geomagnetic response to the CME, by applying innovative data analysis tools that allow to investigate the time variation of ground-based observations of the Earth's magnetic field during the associated geomagnetic storm

Structure and dynamics of the integrin LFA-1 I-domain in the inactive state underlie its inside-out/outside-in signaling and allosteric mechanisms.

Lymphocyte function-associated antigen 1 (LFA-1) is an integrin that transmits information in two directions across the plasma membrane of leukocytes, in so-called outside-in and inside-out signaling mechanisms. To investigate the structural basis of these mechanisms, we studied the conformational space of the apo I-domain using replica-averaged metadynamics simulations in combination with nuclear magnetic resonance chemical shifts. We thus obtained a free energy landscape that reveals the existence of three conformational substates of this domain. The three substates include conformations similar to existing crystallographic structures of the low-affinity I-domain, the inactive I-domain with an allosteric antagonist inhibitor bound underneath α helix 7, and an intermediate affinity state of the I-domain. The multiple substates were validated with residual dipolar coupling measurements. These results suggest that the presence of three substates in the apo I-domain enables the precise regulation of the binding process that is essential for the physiological function of LFA-1.This study was supported by the Wellcome Trust and the BBSRC.This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.str.2014.12.02

Molecular insights into cell toxicity of a novel familial amyloidogenic variant of &#946;2-microglobulin

The first genetic variant of β(2)‐microglobulin (b2M) associated with a familial form of systemic amyloidosis has been recently described. The mutated protein, carrying a substitution of Asp at position 76 with an Asn (D76N b2M), exhibits a strongly enhanced amyloidogenic tendency to aggregate with respect to the wild‐type protein. In this study, we characterized the D76N b2M aggregation path and performed an unprecedented analysis of the biochemical mechanisms underlying aggregate cytotoxicity. We showed that, contrarily to what expected from other amyloid studies, early aggregates of the mutant are not the most toxic species, despite their higher surface hydrophobicity. By modulating ganglioside GM1 content in cell membrane or synthetic lipid bilayers, we confirmed the pivotal role of this lipid as aggregate recruiter favouring their cytotoxicity. We finally observed that the aggregates bind to the cell membrane inducing an alteration of its elasticity (with possible functional unbalance and cytotoxicity) in GM1‐enriched domains only, thus establishing a link between aggregate‐membrane contact and cell damage