Computational Oral Absorption Simulation for Low‐Solubility Compounds

Bile micelles play an important role in oral absorption of low‐solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH–solubility profile in bile micelles, the Henderson–Hasselbalch equation should be modified to take bile‐micelle partition into account. For the dissolution rate, in the Nernst–Brunner equation, the effective diffusion coefficient in bile‐micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8‐ to 18‐fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral‐absorption data of low‐solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed.     

Computational Fluid Dynamics Analysis of Upper Airway Changes after Protraction Headgear and Rapid Maxillary Expansion Treatment

Clinically, it is common for Class III patients with maxillary skeletal deficiency, which may result in a variety of adverse consequences. Protraction headgear and rapid maxillary expansion (PE) is an effective treatment, but its effect on upper airway hydrodynamics has not been reported. The main purpose of this study was to evaluate the changes of the flow in the upper airway after PE by computational fluid dynamics (CFD). The sample includes fifteen patients (6 males, 9 females, age 11.00 ± 1.00) and the paired T-test was used to analyze the differences between the measured data before and after treatment. The maximum flow velocity decreased from 8.42 ± 0.16 m/s to 6.98 ± 0.36 m/s (p < 0.05), and the maximum shear force decreased from 3.72 ± 1.48 Pa to 2.13 ± 0.18 Pa. The maximum negative pressure decreased from −101.78 ± 33.60 Pa to 58.15 ± 9.16 Pa, only the changes of velopharynx and glossopharynx were statistically significant; while the maximum resistance decreased from 140.88 ± 68.68 Pa/mL/s to 45.95 ± 22.96 Pa/mL/s. PE can effectively reduce the airflow resistance of the upper airway and the probability of airway collapse, thus improving the patient’s ventilation function.     

Development and regeneration of the retinotectal map in goldfish: a computational study

We present a simple computational model to study the interplay of activity-dependent and intrinsic processes thought to be involved in the formation of topographic neural projections. Our model consists of two input layers which project to one target layer. The connections between layers are described by a set of synaptic weights. These weights develop according to three interacting developmental rules: (i) an intrinsic fibre-target interaction which generates chemospecific adhesion between afferent fibres and target cells; (ii) an intrinsic fibre-fibre interaction which generates mutual selective adhesion between the afferent fibres; and (iii) an activity-dependent fibre-fibre interaction which implements Hebbian learning. Additionally, constraints are imposed to keep synaptic weights finite. The model is applied to a set of eleven experiments on the regeneration of the retinotectal projection in goldfish. We find that the model is able to reproduce the outcome of an unprecedented range of experiments with the same set of model parameters, including details of the size of receptive and projective fields. We expect this mathematical framework to be a useful tool for the analysis of developmental processes in general. <br>     

Circadian clock effects on cellular proliferation: Insights from theory and experiments

Oscillations of the cellular circadian clock have emerged as an important regulator of many physiological processes, both in health and in disease. One such process, cellular proliferation, is being increasingly recognized to be affected by the circadian clock. Here, we review how a combination of experimental and theoretical work has furthered our understanding of the way circadian clocks couple to the cell cycle and play a role in tissue homeostasis and cancer. Finally, we discuss recently introduced methods for modeling coupling of clocks based on techniques from survival analysis and machine learning and highlight their potential importance for future studies.     

Rational design,synthesis and biological profiling of new KDM4C inhibitors

The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.     

Pressure Drops in a Distensible Model of End-to-side Anastomosis in Systemic-to-pulmonary Shunts

The modified Blalock-Taussig shunt is a surgical procedure used as a palliation to treat complex congenital heart defects. It consists of an interposing prosthetic tube between the innominate/subclavian artery and the right pulmonary artery. Previous experience indicates that the pressure drop across the shunt is affected by the pulmonary pressure at the distal anastomosis combined with the distensibility of the anastomosis. In this study, a computational fluid-structure interaction approach is presented to investigate the haemodynamic behaviour. Steady-state fluid dynamics and structural analyses were carried out using commercial codes based on the finite element method (FIDAP and ABAQUS) coupled by means of a purposely-developed procedure to transfer boundary conditions. Both prosthetic tube and artery walls were characterised by non-linear material properties. Three different pulmonary pressures (2, 5 and 15 mmHg) and two volume flow rates (0.4 and 0.8 l/min) were investigated. Results indicate that the effects of distensibility at the distal anastomosis on the shunt pressure drop are relevant only when the distal anastomosis on the shunt pressure drop are relevant only when the distal anastomosis is not fully distended, which occurs when the pulmonary pressure is lower than 5 mmHg.     

Near Infrared Optical Projection Tomography for Assessments of β-cell Mass Distribution in Diabetes Research

By adapting OPT to include the capability of imaging in the near infrared (NIR) spectrum, we here illustrate the possibility to image larger bodies of pancreatic tissue, such as the rat pancreas, and to increase the number of channels (cell types) that may be studied in a single specimen. We further describe the implementation of a number of computational tools that provide: 1/ accurate positioning of a specimen''s (in our case the pancreas) centre of mass (COM) at the axis of rotation (AR)²; 2/ improved algorithms for post-alignment tuning which prevents geometric distortions during the tomographic reconstruction² and 3/ a protocol for intensity equalization to increase signal to noise ratios in OPT-based BCM determinations³. In addition, we describe a sample holder that minimizes the risk for unintentional movements of the specimen during image acquisition. Together, these protocols enable assessments of BCM distribution and other features, to be performed throughout the volume of intact pancreata or other organs (e.g. in studies of islet transplantation), with a resolution down to the level of individual islets of Langerhans.     

Applying a multiobjective metaheuristic inspired by honey bees to phylogenetic inference

The development of increasingly popular multiobjective metaheuristics has allowed bioinformaticians to deal with optimization problems in computational biology where multiple objective functions must be taken into account. One of the most relevant research topics that can benefit from these techniques is phylogenetic inference. Throughout the years, different researchers have proposed their own view about the reconstruction of ancestral evolutionary relationships among species. As a result, biologists often report different phylogenetic trees from a same dataset when considering distinct optimality principles. In this work, we detail a multiobjective swarm intelligence approach based on the novel Artificial Bee Colony algorithm for inferring phylogenies. The aim of this paper is to propose a complementary view of phylogenetics according to the maximum parsimony and maximum likelihood criteria, in order to generate a set of phylogenetic trees that represent a compromise between these principles. Experimental results on a variety of nucleotide data sets and statistical studies highlight the relevance of the proposal with regard to other multiobjective algorithms and state-of-the-art biological methods.     

Comparing methods for metabolic network analysis and an application to metabolic engineering

Bioinformatics tools have facilitated the reconstruction and analysis of cellular metabolism of various organisms based on information encoded in their genomes. Characterization of cellular metabolism is useful to understand the phenotypic capabilities of these organisms. It has been done quantitatively through the analysis of pathway operations. There are several in silico approaches for analyzing metabolic networks, including structural and stoichiometric analysis, metabolic flux analysis, metabolic control analysis, and several kinetic modeling based analyses. They can serve as a virtual laboratory to give insights into basic principles of cellular functions. This article summarizes the progress and advances in software and algorithm development for metabolic network analysis, along with their applications relevant to cellular physiology, and metabolic engineering with an emphasis on microbial strain optimization. Moreover, it provides a detailed comparative analysis of existing approaches under different categories.     

A study of wall shear stress in 12 aneurysms with respect to different viscosity models and flow conditions

Recent computational fluid dynamics (CFD) studies relate abnormal blood flow to rupture of cerebral aneurysms. However, it is still debated how to model blood flow with sufficient accuracy. Common assumptions made include Newtonian behaviour of blood, traction free outlet boundary conditions and inlet boundary conditions based on available literature. These assumptions are often required since the available patient specific data is usually restricted to the geometry of the aneurysm and the surrounding vasculature. However, the consequences of these assumptions have so far been inadequately addressed.