Stepwise dissection and visualization of the catalytic mechanism of haloalkane dehalogenase LinB using molecular dynamics simulations and computer graphics

The different steps of the dehalogenation reaction carried out by LinB on three different substrates have been characterized using a combination of quantum mechanical calculations and molecular dynamics simulations. This has allowed us to obtain information in atomic detail about each step of the reaction mechanism, that is, substrate entrance and achievement of the near-attack conformation, transition state stabilization within the active site, halide stabilization, water molecule activation and subsequent hydrolytic attack on the ester intermediate with formation of alcohol, and finally product release. Importantly, no bias or external forces were applied during the whole procedure so that both intermediates and products were completely free to sample configuration space in order to adapt to the plasticity of the active site and/or search for an exit. Differences in substrate reactivity were found to be correlated with the ease of adopting the near-attack conformation and two different exit pathways were found for product release that do not interfere with substrate entrance. Additional support for the different entry and exit pathways was independently obtained from an examination of the enzyme's normal modes.     

Information systems for enhancing social experience in a conference context: A sensor based approach

We combine Auto Identification and Web technologies in an extensible on-site event support system for enhancing experience of conference organizers as well as participants. Our system enables users to authenticate themselves using RFID badges and to access interactive, Web-based services via a touchscreen PC. The developed services aim at supporting social interactions of participants, and thus validate the promising usage directions of the combination of offline social networks and the online social Web. The main hypothesis of our work is that: ??A sensor based information system can truly enhance social conference experience.?? Technically, we have investigated employment of Web 2.0 technologies in social, sensor and mobile technologies enabled systems at conferences and events. This article gives an overview of the overall system and its evaluation via a user survey and usage log data collected during the Extended Semantic Web Conference (ESWC) 2010 and similar international conferences, altogether with several hundred participants.     

A Mixed Closure-CSP Method for Solving Scheduling Problems

Scheduling problems can be viewed as a set of temporal metric and disjunctive constraints and so they can be formulated in terms of CSP techniques. In the literature, there are CSP-based methods which sequentially interleave search efforts with the application of consistency enforcing mechanisms and variable/ordering heuristics. Therefore, the number of backtrackings needed to obtain a solution is reduced. In this paper, we propose a new method that effectively integrates the CSP process into a limited closure process: not by interleaving them but rather as a part of the same process. Such an integration allows us to define more informed heuristics. These heuristics are used to limit the complete closure process to a maximum number of disjunctions, thereby reducing its complexity while at the same time reducing the search space. Some open disjunctive solutions can be maintained in the CSP process, limiting the number of backtrackings necessary, and avoiding having to know all the problem constraints in advance. Our experiments with flow-shop and job-shop instances show that this approach obtains a feasible solution/optimal solution without having to use backtracking in most cases. We also analyze the behaviour of our algorithm when some constraints are known dynamically and we demonstrate that it can provide better results than a pure CSP process.     

Non-Gaussian Model for Ringing Phenomena in Offshore Structures

Significant interest has been shown in identifying the nonlinear mechanisms that induce a ringing type response in offshore structural systems. This high frequency transient type response has been observed in offshore systems, particularly in tension leg platforms (TLPs). Given the implications of this behavior on the fatigue life of TLP tendons, it is essential that ringing be considered in the overall response evaluation. This study presents two non-Gaussian probabilistic models of nonlinear viscous hydrodynamic wave forces that induce ringing. The response of a single-degree-of-freedom system exposed to these non-Gaussian wave force models is then evaluated using analytical and numerical studies based on the It? differentiation rule and the Monte Carlo simulation procedure, respectively. The results demonstrate that the proposed models induce ringing type response in a simplified structure. This study provides a probabilistic framework for modeling ringing type phenomenon which will serve as a building block for more refined hydrodynamic load models.     

SARS-CoV-2 Infection Dysregulates Cilia and Basal Cell Homeostasis in the Respiratory Epithelium of Hamsters

Similar to many other respiratory viruses, SARS-CoV-2 targets the ciliated cells of the respiratory epithelium and compromises mucociliary clearance, thereby facilitating spread to the lungs and paving the way for secondary infections. A detailed understanding of mechanism involved in ciliary loss and subsequent regeneration is crucial to assess the possible long-term consequences of COVID-19. The aim of this study was to characterize the sequence of histological and ultrastructural changes observed in the ciliated epithelium during and after SARS-CoV-2 infection in the golden Syrian hamster model. We show that acute infection induces a severe, transient loss of cilia, which is, at least in part, caused by cilia internalization. Internalized cilia colocalize with membrane invaginations, facilitating virus entry into the cell. Infection also results in a progressive decline in cells expressing the regulator of ciliogenesis FOXJ1, which persists beyond virus clearance and the termination of inflammatory changes. Ciliary loss triggers the mobilization of p73⁺ and CK14⁺ basal cells, which ceases after regeneration of the cilia. Although ciliation is restored after two weeks despite the lack of FOXJ1, an increased frequency of cilia with ultrastructural alterations indicative of secondary ciliary dyskinesia is observed. In summary, the work provides new insights into SARS-CoV-2 pathogenesis and expands our understanding of virally induced damage to defense mechanisms in the conducting airways.     

Primary Aldosteronism and Resistant Hypertension: A Pathophysiological Insight

Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most common cause of secondary hypertension. Its prevalence increases with the severity of hypertension, reaching up to 29.1% in patients with resistant hypertension (RH). Both PA and RH are “high-risk phenotypes”, associated with increased cardiovascular morbidity and mortality compared to non-PA and non-RH patients. Aldosterone excess, as occurs in PA, can contribute to the development of a RH phenotype through several mechanisms. First, inappropriate aldosterone levels with respect to the hydro-electrolytic status of the individual can cause salt retention and volume expansion by inducing sodium and water reabsorption in the kidney. Moreover, a growing body of evidence has highlighted the detrimental consequences of “non-classical” effects of aldosterone in several target tissues. Aldosterone-induced vascular remodeling, sympathetic overactivity, insulin resistance, and adipose tissue dysfunction can further contribute to the worsening of arterial hypertension and to the development of drug-resistance. In addition, the pro-oxidative, pro-fibrotic, and pro-inflammatory effects of aldosterone may aggravate end-organ damage, thereby perpetuating a vicious cycle that eventually leads to a more severe hypertensive phenotype. Finally, neither the pathophysiological mechanisms mediating aldosterone-driven blood pressure rise, nor those mediating aldosterone-driven end-organ damage, are specifically blocked by standard first-line anti-hypertensive drugs, which might further account for the drug-resistant phenotype that frequently characterizes PA patients.     

A genetic algorithm for energy-efficiency in job-shop scheduling

Many real-world scheduling problems are solved to obtain optimal solutions in term of processing time, cost, and quality as optimization objectives. Currently, energy-efficiency is also taken into consideration in these problems. However, this problem is NP-hard, so many search techniques are not able to obtain a solution in a reasonable time. In this paper, a genetic algorithm is developed to solve an extended version of the Job-shop Scheduling Problem in which machines can consume different amounts of energy to process tasks at different rates (speed scaling). This problem represents an extension of the classical job-shop scheduling problem, where each operation has to be executed by one machine and this machine can work at different speeds. The evaluation section shows that a powerful commercial tool for solving scheduling problems was not able to solve large instances in a reasonable time, meanwhile our genetic algorithm was able to solve all instances with a good solution quality.