Synthesis and biological evaluation of crown ether acyl derivatives

Peer reviewe

Imbalances in serum angiopoietin concentrations are early predictors of septic shock development in patients with post chemotherapy febrile neutropenia

Background: Febrile neutropenia carries a high risk of sepsis complications, and the identification of biomarkers capable to identify high risk patients is a great challenge. Angiopoietins (Ang -) are cytokines involved in the control microvascular permeability. It is accepted that Ang-1 expression maintains endothelial barrier integrity, and that Ang-2 acts as an antagonizing cytokine with barrier-disrupting functions in inflammatory situations. Ang-2 levels have been recently correlated with sepsis mortality in intensive care units. Methods: We prospectively evaluated concentrations of Ang-1 and Ang-2 at different time-points during febrile neutropenia, and explored the diagnostic accuracy of these mediators as potential predictors of poor outcome in this clinical setting before the development of sepsis complications. Results: Patients that evolved with septic shock (n = 10) presented higher levels of Ang-2 measured 48 hours after fever onset, and of the Ang-2/Ang-1 ratio at the time of fever onset compared to patients with non-complicated sepsis (n = 31). These levels correlated with sepsis severity scores. Conclusions: Our data suggest that imbalances in the concentrations of Ang-1 and Ang-2 are independent and early markers of the risk of developing septic shock and of sepsis mortality in febrile neutropenia, and larger studies are warranted to validate their clinical usefulness. Therapeutic strategies that manipulate this Ang-2/Ang-1 imbalance can potentially offer new and promising treatments for sepsis in febrile neutropenia

Determination of Conformational Equilibria in Proteins Using Residual Dipolar Couplings

In order to carry out their functions, proteins often undergo significant conformational fluctuations that enable them to interact with their partners. The accurate characterization of these motions is key in order to understand the mechanisms by which macromolecular recognition events take place. Nuclear magnetic resonance spectroscopy offers a variety of powerful methods to achieve this result. We discuss a method of using residual dipolar couplings as replica-averaged restraints in molecular dynamics simulations to determine large amplitude motions of proteins, including those involved in the conformational equilibria that are established through interconversions between different states. By applying this method to ribonuclease A, we show that it enables one to characterize the ample fluctuations in interdomain orientations expected to play an important functional role

Trends in template/fragment-free protein structure prediction

Predicting the structure of a protein from its amino acid sequence is a long-standing unsolved problem in computational biology. Its solution would be of both fundamental and practical importance as the gap between the number of known sequences and the number of experimentally solved structures widens rapidly. Currently, the most successful approaches are based on fragment/template reassembly. Lacking progress in template-free structure prediction calls for novel ideas and approaches. This article reviews trends in the development of physical and specific knowledge-based energy functions as well as sampling techniques for fragment-free structure prediction. Recent physical- and knowledge-based studies demonstrated that it is possible to sample and predict highly accurate protein structures without borrowing native fragments from known protein structures. These emerging approaches with fully flexible sampling have the potential to move the field forward

Hysteretic Damping as an Energy Parameter in Gigacycle Fatigue

The mechanical behaviour of materials subjected to dynamic loading is now a classical subject but is still a big challenge. The fatigue limit of the materials, defined as the maximum dynamic load amplitude level for which no fatigue failures occur, has been set for a number of load cycles up to 10E7. Extending this limit with the traditional hardware is a much more difficult technical task due to the length of time needed for the completion of tests, but there is a real industrial concern about this subject due to the growing need to extend the lifecycle of some structures beyond such limits. Therefore, the study of fatigue is being extended to more than 10E7 cycles, typically 10E9 and more, in a new area of studies known as gigacycle fatigue. It is within this framework that the study presented in this paper fits. The approach here presented is based on the fact that the fatigue problem can be understood in terms of the energy available for irreversible process triggering. This energy will be involved in micro-structural irreversible changes in the material before being dissipated as thermal energy. The energy needed to trigger such changes must come from the dynamic loading. In fact, the balance between the energy supplied to and returned by the material is positive and the hysteretic damping factor represents the inelastic fraction of energy balance for each cycle.Final Accepted Versio

Estimation of the rotational terms of the dynamic response matrix

The dynamic response of a structure can be described by both its translational and rotational receptances. The latter ones are frequently not considered because of the difficulties in applying a pure moment excitation or in measuring rotations. However, in general, this implies a reduction up to 75% of the complete model. On the other hand, if a modification includes a rotational inertia, the rotational receptances of the unmodified system are needed. In one method, more commonly found in the literature, a so called T-block is attached to the structure. Then, a force, applied to an arm of the T-block, generates a moment together with a force at the connection point. The T-block also allows for angular displacement measurements. Nevertheless, the results are often not quite satisfactory. In this work, an alternative method based upon coupling techniques is developed, in which rotational receptances are estimated without the need of applying a moment excitation. This is accomplished by introducing a rotational inertia modification when rotating the T-block. The force is then applied in its centroid. Several numerical and experimental examples are discussed so that the methodology can be clearly described. The advantages and limitations are identified within the practical application of the methodPeer reviewedSubmitted Versio