Towards Automated Binding Affinity Prediction Using an Iterative Linear Interaction Energy Approach

Binding affinity prediction of potential drugs to target and off-target proteins is an essential asset in drug development. These predictions require the calculation of binding free energies. In such calculations, it is a major challenge to properly account for both the dynamic nature of the protein and the possible variety of ligand-binding orientations, while keeping computational costs tractable. Recently, an iterative Linear Interaction Energy (LIE) approach was introduced, in which results from multiple simulations of a protein-ligand complex are combined into a single binding free energy using a Boltzmann weighting-based scheme. This method was shown to reach experimental accuracy for flexible proteins while retaining the computational efficiency of the general LIE approach. Here, we show that the iterative LIE approach can be used to predict binding affinities in an automated way. A workflow was designed using preselected protein conformations, automated ligand docking and clustering, and a (semi-)automated molecular dynamics simulation setup. We show that using this workflow, binding affinities of aryloxypropanolamines to the malleable Cytochrome P450 2D6 enzyme can be predicted without a priori knowledge of dominant protein-ligand conformations. In addition, we provide an outlook for an approach to assess the quality of the LIE predictions, based on simulation outcomes only.     

Stokes-Anti-Stokes Iterative Resonator Method for Modeling Raman Lasers

We present a novel modeling method to describe the steady-state and transient regimes of a continuous-wave pumped Raman laser emitting both Stokes and anti-Stokes photons. Our so-called "Stokes-anti-Stokes iterative resonator method" evaluates for every half round-trip time the longitudinal distribution of the intracavity pump, Stokes and anti-Stokes fields propagating in forward and backward directions. Although this Stokes-anti-Stokes iterative resonator method is widely applicable, its most important asset resides in its ability to accurately model Raman lasers that feature cavity enhancement of the pump power and that emit both Stokes and anti-Stokes photons. Important here is that our modeling method correctly incorporates the longitudinal intracavity field distributions, the generation of anti-Stokes photons, and the interference effects between incident and intracavity pump fields, and that it describes not only the lasers' steady-state operation but also their transient characteristics. We demonstrate for both a hydrogen-based and a silicon-based Raman laser with pump cavity enhancement that the Stokes-anti-Stokes iterative resonator method performs better than the modeling methods presently used for these categories of Raman lasers. Finally, to demonstrate the potentialities of our modeling method, we numerically simulate, for the first time according to our knowledge, the anti-Stokes emission generated by a silicon-based Raman laser     

Cellular uncoupling during ischemia in hypertrophied and failing rabbit ventricular myocardium: effects of preconditioning

BACKGROUND: Patients with heart failure show a very high incidence of arrhythmias and sudden death that is often preceded by ischemia; however, data on electrophysiological changes during ischemia in failing myocardium are sparse. We studied electrical uncoupling during ischemia in normal and failing myocardium. METHODS AND RESULTS: Tissue resistance, intracellular Ca2+ concentration (Indo-1 fluorescence ratio), and mechanical activity were simultaneously determined in arterially perfused right ventricular papillary muscles from 11 normal and 15 failing rabbits. Heart failure was induced by combined volume and pressure overload. Before sustained ischemia, muscles were subjected to control perfusion (non-PC) or ischemic preconditioning (PC). The onset of uncoupling during ischemia was equal in non-PC normal (13.6+/-0.9 minutes of ischemia) and non-PC failing hearts (13.3+/-0.7 minutes of ischemia). PC postponed uncoupling in normal hearts by 10 minutes. In failing hearts, however, PC caused a large variability in the onset of uncoupling during ischemia (mean, 12.2+/-2.1; range, 5 to 22 minutes of ischemia). The duration of uncoupling process was prolonged in failing hearts (12.9+/-0.9 minutes) compared with normal hearts (7.8+/-0.4 minutes). The degree of heart failure and relative heart weight of the failing hearts significantly correlated with the earlier uncoupling after PC and the duration of uncoupling. In every experiment, the start of Ca2+ rise and contracture preceded uncoupling during ischemia. CONCLUSIONS: The duration of the process of ischemia-induced electrical uncoupling in failing hearts is prolonged compared with that in normal hearts. Ischemic PC has detrimental effects in severely failing papillary muscles because it advances the moment of irreversible ischemic damage.     

Spin-Wave Modes and Spin Diffusion Anisotropy in a 3He-4He Mixture at High B/T

We present nmr measurements in a 6.2% ³ He- ⁴ He mixture carried out at 11.3 T with temperatures down to 3.5 mK, yielding a very high B/T ratio. We have measured the transverse spin diffusion with the spin-echo technique. We observe a saturation of the spin diffusion coefficient at low temperature corresponding to an anisotropy temperature T_a13mK. Using the same setup, we were able to excite Silin spin-wave modes in the experimental cell.     

What stimulates teachers to integrate ICT in their pedagogical practices? The use of digital learning materials in education

The question ‘What stimulates teachers to integrate Information and Communication Technologies (ICTs) in their pedagogical practices?’ was addressed in the context of teachers’ usage of digital learning materials (DLMs). We adopted Fishbein’s Integrative Model of Behavior Prediction (IMBP), to investigate the various relationships between distal and proximal variables and intention. Mediation analysis revealed that the proximal variables attitude, subjective norm, and self-efficacy towards DLMs were significant predictors of teachers’ intention to use DLMs. The contribution of subjective norm, however, was modest. Attitude, subjective norm and self-efficacy mediated the effects of the following three distal variables on intention: previous use of DLMs, perceived knowledge and skills to use DLMs, and colleagues’ usage of DLMs. Persuasive communication and skills based training seem, therefore, appropriate interventions to promote a positive attitude towards DLMs and improve self-efficacy in using DLMs.     

Declining gonadal function in elderly men

Ageing in men is accompanied by a progressive decline of gonadal function with, in particular, a decline of total and free testosterone (T) plasma levels resulting in a significant proportion of elderly men over age 60 years presenting with subnormal T levels compared with the levels in young adults. A great interindividual variation in T levels is observed in elderly men, a variability explained in part by physiological variables and differences in life style, while associated acute or chronic diseases may accentuate the age-related decline of T levels. The progressive decrease of plasma T levels has been shown to result from both primary testicular changes and altered neuroendocrine regulation of Leydig cell function. At present, little is known about the clinical relevance of the relative hypoandrogenism of elderly men and there is an urgent need for more longitudinal studies, which may clarify a possible role of decreased T levels in the modulation of the clinical consequences of ageing in men. In view of the lack of relevant controlled clinical trials having careful assessment of the risks and benefits of androgen replacement therapy in elderly men, this treatment should be reserved for selected patients with clinically and biochemically manifest hypogonadism, after careful screening for contraindications.     

Overview of solar cell technologies and results on high efficiency multicrystalline silicon substrates

Fabrication technologies for multicrystalline silicon (mc-Si) solar cells have advanced in recent years with efficiencies of mc-Si cells exceeding 18%. Intense efforts have been made at laboratory level to improve process technology, growth methods, and material improvement techniques to deliver better devices at lower cost. Deeper understanding of the physics and optics of the device led to improved device design. This provided a fruitful feedback to the industrial sector. Both screenprinting and buried-contact technologies yield cells of high performance. An increasingly large amount of research activity is also focussed on the fabrication of thin solar cells on cheap substrates such as glass, ceramic, or low quality silicon. Success of these efforts is expected to lead to high efficiency devices at much lower costs. Efforts are also being put on low thermal budget processing of solar cells based on rapid thermal annealing.     

Evaluation of a semi-cylindrical solenoid as an applicator forradio-frequency hyperthermia

A modified solenoid having a semi-circular cross section is evaluated as an applicator for radio-frequency heating of biological materials. The operating efficiency of this applicator and the distribution of the electric field established within a simulated biological sample are determined for a number of modes of excitation. It is shown that uniform heating to a substantial depth is possible at efficiencies in excess of 80 percent.