Higher-Order Methods for Differential Inclusions

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Late outcomes of a randomized trial of high-frequency oscillation in neonates

BACKGROUND: Results from an observational study involving neonates suggested that high-frequency oscillatory ventilation (HFOV), as compared with conventional ventilation, was associated with superior small-airway function at follow-up. Data from randomized trials are needed to confirm this finding. METHODS: We studied 319 adolescents who had been born before 29 weeks of gestation and had been enrolled in a multicenter, randomized trial that compared HFOV with conventional ventilation immediately after birth. The trial involved 797 neonates, of whom 592 survived to hospital discharge. We compared follow-up data from adolescents who had been randomly assigned to HFOV with follow-up data from those who had been randomly assigned to conventional ventilation, with respect to lung function and respiratory health, health-related quality of life, and functional status, as assessed with the use of questionnaires completed when the participants were 11 to 14 years of age. The primary outcome was forced expiratory flow at 75% of the expired vital capacity (FEF(75)). RESULTS: The HFOV group had superior results on a test of small-airway function (z score for FEF(75), −0.97 with HFOV vs. −1.19 with conventional therapy; adjusted difference, 0.23 [95% confidence interval, 0.02 to 0.45]). There were significant differences in favor of HFOV in several other measures of respiratory function, including forced expiratory volume in 1 second, forced vital capacity, peak expiratory flow, diffusing capacity, and impulse-oscillometric findings. As compared with the conventional-therapy group, the HFOV group had significantly higher ratings from teachers in three of eight school subjects assessed, but there were no other significant differences in functional outcomes. CONCLUSIONS: In a randomized trial involving children who had been born extremely prematurely, those who had undergone HFOV, as compared with those who had received conventional ventilation, had superior lung function at 11 to 14 years of age, with no evidence of poorer functional outcomes. (Funded by the National Institute for Health Research Health Technology Assessment Programme and others.

Exploring the Conformational Landscape of Bioactive Small Molecules

By using a combination of classical Hamiltonian replica exchange with high-level quantum mechanical calculations on more than one hundred drug-like molecules, we explored here the energy cost associated with binding of drug-like molecules to target macromolecules. We found that, in general, the drug-like molecules present bound to proteins in the Protein Data Bank (PDB) can access easily the bioactive conformation and in fact for 73% of the studied molecules the bioactiveconformation is within 3kBT from the most-stable conformation in solution as determined by DFT/SCRF calculations. Cases with large differences between the most-stable and the bioactive conformations appear in ligands recognized by ionic contacts, or very large structures establishing many favorable interactions with the protein. There are also a few cases where we observed a non-negligible uncertainty related to the experimental structure deposited in PDB. Remarkably, the rough automatic force field used here provides reasonable estimates of the conformational ensemble of drugs in solution. The outlined protocol can be used to better estimate the cost of adopting the bioactive conformation

Bioactive conformational ensemble server and database. A public framework to speed up in silico drug discovery.

Modern high-throughput structure-based drug discovery algorithms consider ligand flexibility, but typically with low accuracy, which results in a loss of performance in the derived models. Here we present the Bioactive Conformational Ensemble (BCE) server and its associated database. The server creates conformational ensembles of drug-like ligands and stores them in the BCE database, where a variety of analyses are offered to the user. The workflow implemented in the BCE server combines enhanced sampling molecular dynamics with self-consistent reaction field quantum mechanics (SCRF/QM) calculations. The server automatizes all the steps to transform 1D or 2D representation of drugs into three dimensional molecules, which are then titrated, parametrized, hydrated and optimized before being subjected to Hamiltonian replica-exchange (HREX) molecular dynamics simulations. Ensembles are collected and subjected to a clustering procedure to derive representative conformers, which are then analyzed at the SCRF/QM level of theory. All structural data is organized in a noSQL database accessible through a graphical interface and in a programmatic manner through a REST API. The server allows the user to define a private workspace and offers a deposition protocol as well as input files for "in house" calculations in those cases where confidentiality is a must. The database and the associated server are available at https://mmb.irbbarcelona.org/BC

DFFR: A New Method for High-Throughput Recalibration of Automatic Force-Fields for Drugs

We present drug force-field recalibration (DFFR), a new method for refining of automatic force-fields used to represent small drugs in docking and molecular dynamics simulations. The method is based on fine-tuning of torsional terms to obtain ensembles that reproduce observables derived from reference data. DFFR is fast and flexible and can be easily automatized for a high-throughput regime, making it useful in drug-design projects. We tested the performance of the method in a few model systems and also in a variety of druglike molecules using reference data derived from: (i) density functional theory coupled to a self-consistent reaction field (DFT/SCRF) calculations on highly populated conformers and (ii) enhanced sampling quantum mechanical/molecular mechanics (QM/MM) where the drug is reproduced at the QM level, while the solvent is represented by classical force-fields. Extension of the method to include other sources of reference data is discussed

Anthropometric study of the facial index in the population of Central Serbia

The aim of this study was to determine the craniofacial parameters in the population of the central part of Serbia. The research was conducted on 700 persons (360 males and 340 females), aged 18-65 years, selected randomly. The measured parameters were morphological facial height and breadth. The standard spreading caliper with scale was used for the measurement of facial parameters. There were significant differences in the facial parameters of male compared to female subjects in all observed parameters. The mean value of the morphological facial height in the study population was 116.8 mm ± 7.28, maximum facial breadth 124.12 mm ± 8.44, while the mean value of the total facial index was 93.68 ± 6.86. The total facial index was calculated according to the formula and the obtained results were analyzed statistically using the t-test. The dominant phenotype in the studied population was leptoprosopic. The data obtained in our study may be useful in anthropological research, forensics, genetic research, as well as in medical clinical practice

Surface integrity of mild steel in wire electrical discharge machining

This project deals with machining Mild Steel work piece using Wire Electric Discharge Machine (WEDM). The objective of the project is to determine the surface integrity of material when machining with different parameters. In this particular project, five parameters are being used which are on time, off time, peak current, servo voltage and wire speeds. From the experiment, the surface roughness was measured using perthometer. The machining of Mild Steel work piece was performs using Wire-EDM Sodick AQ535L. Then, the analysis was done using the Statistica software. By doing this project using WEDM for mild steel AISI 1020, it will aid people to estimate the surface roughness for selected parameters and avoid using try and error method. From the analysis, on time and peak current are the significance parameters to the mild steel’s surface roughness. The lower value of on time and peak current used,, the result for surface roughness are better. By considers all of these parameters, the good machining condition can be performed

Attractors in Dynamics with Choice

Dynamics with choice is a generalization of discrete-time dynamics where instead of the same evolution operator at every time step there is a choice of operators to transform the current state of the system. Many real life processes studied in chemical physics, engineering, biology and medicine, from autocatalytic reaction systems to switched systems to cellular biochemical processes to malaria transmission in urban environments, exhibit the properties described by dynamics with choice. We study the long-term behavior in dynamics with choice. We prove very general results on the existence and properties of global compact attractors in dynamics with choice. In addition, we study the dynamics with restricted choice when the allowed sequences of operators correspond to subshifts of the full shift. One of practical consequences of our results is that when the parameters of a discrete-time system are not known exactly and/or are subject to change due to internal instability, or a strategy, or Nature\u27s intervention, the long term behavior of the system may not be correctly described by a system with averaged values for the parameters. There may be a Gestalt effect