How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex.

BACKGROUND: Neuronal migration, the process by which neurons migrate from their place of origin to their final position in the brain, is a central process for normal brain development and function. Advances in experimental techniques have revealed much about many of the molecular components involved in this process. Notwithstanding these advances, how the molecular machinery works together to govern the migration process has yet to be fully understood. Here we present a computational model of neuronal migration, in which four key molecular entities, Lis1, DCX, Reelin and GABA, form a molecular program that mediates the migration process. RESULTS: The model simulated the dynamic migration process, consistent with in-vivo observations of morphological, cellular and population-level phenomena. Specifically, the model reproduced migration phases, cellular dynamics and population distributions that concur with experimental observations in normal neuronal development. We tested the model under reduced activity of Lis1 and DCX and found an aberrant development similar to observations in Lis1 and DCX silencing expression experiments. Analysis of the model gave rise to unforeseen insights that could guide future experimental study. Specifically: (1) the model revealed the possibility that under conditions of Lis1 reduced expression, neurons experience an oscillatory neuron-glial association prior to the multipolar stage; and (2) we hypothesized that observed morphology variations in rats and mice may be explained by a single difference in the way that Lis1 and DCX stimulate bipolar motility. From this we make the following predictions: (1) under reduced Lis1 and enhanced DCX expression, we predict a reduced bipolar migration in rats, and (2) under enhanced DCX expression in mice we predict a normal or a higher bipolar migration. CONCLUSIONS: We present here a system-wide computational model of neuronal migration that integrates theory and data within a precise, testable framework. Our model accounts for a range of observable behaviors and affords a computational framework to study aspects of neuronal migration as a complex process that is driven by a relatively simple molecular program. Analysis of the model generated new hypotheses and yet unobserved phenomena that may guide future experimental studies. This paper thus reports a first step toward a comprehensive in-silico model of neuronal migration.

On-line topographic analysis in the SEM

A novel method for on-line topographic analysis of rough surfaces in the SEM has been investigated. It utilises a digital minicomputer configured to act as a programmable scan generator and automatic focusing unit. The computer is coupled to the microscope through digital-to-analogue converters which enable it to generate ramp waveforms allowing the beam to be scanned over a small sub-region of the field under program control. A further digital-to-analogue converter regulates the current supply to the objective lens of the microscope. The video signal is sampled by means of an analogue-to-digital converter and the resultant binary code stored in the computer's memory as an array of numbers describing relative image intensity. Computations based on the intensity gradient of the image allow the objective lens current to be found for the in-focus condition, which may be related to the working distance through a previous calibration experiment. The sensitivity of the method for detecting small height changes is theoretically of the order of 1 μm. In practice the operator specifies features of interest by means of a mobile spot cursor injected into the SEM display screen, or he may scan the specimen at sub-regions corresponding to pre-determined points on a regular grid defined by him. The operation then proceeds under program control. | A novel method for on-line topographic analysis of rough surfaces in the SEM has been investigated. It utilizes a digital minicomputer configured to act as a programmable scan generator and automatic focusing unit. A further digital-to-analog converter regulates the current supply to the objective lens of the microscope. The video signal is sampled by means of an analog-to-digital converter and the resultant binary code stored in the computer's memory as an array of numbers describing relative image intensity. The sensitivity of the method for detecting small height changes is theroretically of the order of 1 mu m.

Topographical analysis in the SEM using an automatic focusing technique

A novel technique for automated topographical analysis in the SEM has been investigated. It utilizes a 16-bit minicomputer arranged to act as an automatic focusing unit. The computer is coupled to the objective lens of the microscope, by means of a digital to analogue converter, and may regulate the excitation of the lens under program control. Further digital-to-analogue converters allow the computer to act as a programmable scan generator by applying ramp waveforms to the scan amplifiers, permitting the beam to be swept over a small sub-region of the field of interest. The video signal is sampled and applied to an analogue-to-digital converter; the resultant binary numbers are stored in computer memory as an array of values representing relative image intensities within a subregion. A differencing algorithm applied to the collected data allows the level of objective lens excitation to be found at which the sharpness of the image is optimized, and the excitation may be related to the working distance for that subregion through a previous calibration experiment. The sensitivity of the method for detecting small height changes is theoretically of the order of 1 μm.

CLADP - THE CAMBRIDGE LINEAR ANALYSIS AND DESIGN PROGRAMS USER REFERENCE MANUAL (4TH ISSUE: APRIL 1983).

CLADP is an engineering software program developed at Cambridge University for the interactive computer aided design of feedback control systems. CLADP contains a wide range of tools for the analysis of complex systems, and the assessment of their performance when feedback control is applied, thus enabling control systems to be designed to meet difficult performance objectives. The range of tools within CLADP include the latest techniques in the field whose central theme is the extension of classical frequency domain concepts (well known and well proven for single loop systems) to multivariable or multiloop systems, and by making extensive use of graphical presentation information is provided in a readily understood form.

Automated meshing for aero-thermal analysis of complex automotive geometries

Successful product development, especially in motorsport, increasingly depends not just on the ability to simulate aero-thermal behavior of complex geometrical configurations, but also the ability to automate these simulations within a workflow and perform as many simulations as possible within constrained time frames. The core of these aero-thermal simulations - and usually the main bottleneck - is generating the computational mesh. This paper describes recent work aimed at developing a mesh generator which can reliably produce meshes for geometries of essentially arbitrary complexity in an automated manner and fast enough to keep up with the pace of an engineering development program. Our goal is to be able to script the mesh generation within an automated workflow - and forget it. © 2011 SAE International.

Thermal-creep analysis of concrete bridges

The creep effects on sequentially built bridges are analysed by the theory of thermal creep. Two types of analysis are used: time dependent and steady state. The traditional uniform creep analysis is also introduced briefly. Both simplified and parabolic normalising creep-temperature functions are used in the analysis for comparison. Numerical examples are presented, calculated by a computer program based on the theory of thermal creep and using the displacement method. It is concluded that different assumptions within thermal creep can lead to very different results when compared with uniform creep analysis. The steady-state analysis of monolithically built structures can serve as a limit to evaluate total creep effects for both monolithically and sequentially built structures. The importance of the correct selection of the normalising creep-temperature function is demonstrated.

Change propagation analysis in complex technical systems

Understanding how and why changes propagate during engineering design is critical because most products and systems emerge from predecessors and not through clean sheet design. This paper applies change propagation analysis methods and extends prior reasoning through examination of a large data set from industry including 41,500 change requests, spanning 8 years during the design of a complex sensor system. Different methods are used to analyze the data and the results are compared to each other and evaluated in the context of previous findings. In particular the networks of connected parent, child and sibling changes are resolved over time and mapped to 46 subsystem areas. A normalized change propagation index (CPI) is then developed, showing the relative strength of each area on the absorber-multiplier spectrum between -1 and +1. Multipliers send out more changes than they receive and are good candidates for more focused change management. Another interesting finding is the quantitative confirmation of the "ripple" change pattern. Unlike the earlier prediction, however, it was found that the peak of cyclical change activity occurred late in the program driven by systems integration and functional testing. Patterns emerged from the data and offer clear implications for technical change management approaches in system design. Copyright © 2007 by ASME.

A critical analysis of loudness calculation methods

The physical meaning and calculation procedures for determining loudness was critically analyzed. Four noise sources were used in comparing the software packages dBFA dBSonic, which were used in the investigation to a public domain code. The purpose of the comparison was to evaluate the validity of the results obtained and to gain an idea of the shortcomings of the relevant standards. A comparison of the results for loudness was computed from various methods, used in the study. Two basic sources of input data such as a sound level meter (SLM) and a 01 dB data acquisition system (DAQ), were available for the comparison. The SLM directly gave 1/3 octave band levels, while the data from the DAQ was filtered to give the results. Five processing methods, including a Visual Basic (VB) program and a VB program adapted from dBFA, were used for the study. It was found that the calculation of loudness from 1/3 octave cannot be separated from the filtering process.

Generalized power method for sparse principal component analysis

In this paper we develop a new approach to sparse principal component analysis (sparse PCA). We propose two single-unit and two block optimization formulations of the sparse PCA problem, aimed at extracting a single sparse dominant principal component of a data matrix, or more components at once, respectively. While the initial formulations involve nonconvex functions, and are therefore computationally intractable, we rewrite them into the form of an optimization program involving maximization of a convex function on a compact set. The dimension of the search space is decreased enormously if the data matrix has many more columns (variables) than rows. We then propose and analyze a simple gradient method suited for the task. It appears that our algorithm has best convergence properties in the case when either the objective function or the feasible set are strongly convex, which is the case with our single-unit formulations and can be enforced in the block case. Finally, we demonstrate numerically on a set of random and gene expression test problems that our approach outperforms existing algorithms both in quality of the obtained solution and in computational speed. © 2010 Michel Journée, Yurii Nesterov, Peter Richtárik and Rodolphe Sepulchre.