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Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

This paper reviews and extends a technique to detect weak coupling (one-way coupling or complete decoupling) among elements of a dynamic system model, and to partition and reduce models in which weak coupling is found. The ability to partition a model increases the potential for physical-domain model reduction, and allows parallel simulation of smaller individual submodels that can reduce computation time. Negligible constraint equation terms are identified and eliminated in a bond graph by converting inactive power bonds to modulated sources. If separate bond graphs result, between which all modulating signals move from a "driving" subgraph to a "driven" one, then one-way coupling exists in the model and it can be separated into driving and driven partitions. Information flow between the subgraphs is one-way. In this paper the algorithm is extended to models in which two-way information flow from modulating signals precludes complete partitioning. It is shown for several classes of modulating signals that, under certain conditions the signal is "weak" and therefore can be eliminated. Removal of weak signals allows partitioning of the longitudinal and pitch dynamics of a medium-duty truck model. The intensity of dynamic coupling and the potential for model reduction are shown to depend on the magnitude of system parameters and the severity of inputs such as road roughness. © 2007 Elsevier B.V. All rights reserved. 17 271 292 271-292

Previous research has demonstrated that bond graphs are a natural and convenient representation to implement energy-based metrics that evaluate the relative ‘value’ of energy elements in a dynamic system model. Bond graphs also provide a framework for systematically reformulating a reduced bond graph model (and thus the state equations) of the system that results from eliminating the ‘unimportant’ elements. This paper shows that bond graphs also provide a natural and convenient representation for developing a rigorous approach for interpreting the removal of ideal energy elements from the system model. For example, when a generalized inductance in the mechanical domain is eliminated from a model, the bond graph shows whether the coordinate representing the motion of the body becomes free to move (zero inertia) or fixed to ground (infinite inertia). This systematic interpretation of element removal makes bond graphs an attractive modelling language for automated model reduction techniques. An illustrative example is provided to demonstrate how the developed approach can be applied to provide the physical interpretation of energy element removal from a mechanical system.

The chromatin remodeling complex SWI/SNF and the transcription factor C/EBPβ play critical roles in osteoblastic cells as they jointly control transcription of a number of bone‐related target genes. The largest C/EBPβ isoform, LAP*, possesses a short addi

The chromatin remodeling complex SWI/SNF and the transcription factor C/EBPβ play critical roles in osteoblastic cells as they jointly control transcription of a number of bone-related target genes. The largest C/EBPβ isoform, LAP*, possesses a short addi

Commercial competition demands a reduction in the development time of new products. While it has been recognized for a number of years that the development process can be accelerated with the use of computer simulation based on mathematical models of the product, the lack of appropriate modeling tools has limited the effectiveness of this approach. It is the premise of this work that a new modeling metric able to handle nonlinear dynamic systems and all types of energy elements, will improve the effectiveness of modeling tools. A new modeling metric, activity, which is based on energy, is developed in this work. This metric is used to rank the importance of all energy elements in a system. The ranking of the energy elements provides the relative importance of the model parameters and this information can be used to reduce the size of the model. The metric is implemented in an algorithm called Model Order Reduction Algorithm (MORA). MORA is applied to a nonlinear quarter car model showing that elements with low activity can be eliminated without any significant change in model accuracy. MORA is also applied to linear systems, where the steady state activity to sinusoidal inputs is considered. It is shown that the activity varies with frequency, and thus, a series of reduced models can be generated as a function of the excitation frequency. For multibody systems, the activity metric can be applied to each DOF of the rigid bodies. The activity metric is applied to a heavy-duty tractor-semitrailer to demonstrate that a significant number of the model parameters are insignificant, and therefore, that a substantial reduction in the model size can be achieved. Finally, an interpretation algorithm based on the activity metric is developed to provide the user with physical meaning of each low activity element eliminated. In addition, the use of the activity metric to rank the energy elements augments the insight into the model, since the engineer can focus on a smaller number of elements that are identified by MORA as important to the system behavior. In conclusion, this work develops an automated modeling algorithm, MORA, which can be used to rank model parameter importance, reduce model complexity and help provide physical insight into a system. MORA extends the applicability of automated modeling to systems that can be represented by nonlinear dynamic models and it should improve the use of modeling and simulation for product development.

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The Milliken Moment Method (MMM) is a way of efficiently organizing the results from a kinematically constrained vehicle test. Using the MMM and closed-loop dynamic simulation, the authors present a new method for evaluating vehicle handling, where the MMM assesses the overall performance capability of the vehicle, and the simulation determines how much of that performance is used for a closed-loop maneuver. By mapping the simulation data onto the yaw moment - lateral acceleration diagram from the MMM, this method allows a design engineer to explicitly quantify the tradeoff between the controllability and stability of a vehicle. Results from a design case study and comparison of the stability measure to phase plane analysis show that this method captures the tradeoff in design, and clearly represents the overall capability of the driver-vehicle system. Copyright © 2004 by ASME. 73 173 180 173-180

Accurate estimation of engine vibrations is essential in the design of new engines, engine mounts, and the vehicle frames to which they are attached. Mount force prediction has traditionally been simplified by assuming that the reciprocating dynamics of the engine can be deconpled from the three-dimensional motion of the block. The accuracy of the resulting one-way coupled models decreases as engine imbalance and cylinder-to-cylinder variations increase. Further the form of the one-way coupled model must be assumed a priori, and there is no mechanism for generating an intermediate-complexity model if the one-way coupled model has insufficient fidelity. In this paper a new dynamic system model decoupling algorithm is applied to a Detroit Diesel Series 60 in-line six-cylinder engine model to test one-way coupling assumptions and to automate generation of a proper model for mount force prediction. The algorithm, which identifies and removes unnecessary constraint equation terms, is reviewed with the aid of an illustrative example. A fully coupled, balanced rigid body model with no cylinder-to-cylinder variations is then constructed, from which x, y, and z force components at the left-rear, right-rear and front engine mounts are predicted. The decoupling algorithm is then applied to automatically generate a reduced model in which reciprocating dynamics and gross block motion are decoupled. The amplitudes of the varying components of the force time series are predicted to within 8%, with computation time reduced by 55%. The combustion pressure profile in one cylinder is then changed to represent a misfire that creates imbalance. The decoupled model generated by the algorithm is significantly more robust to imbalance than the traditional one-way coupled models in the literature however, the vertical component of the front mount force is poorly predicted. Reapplication of the algorithm identifies constraint equation terms that must be reinstated. A new, nondecoupled model is generated that accurately predicts all mount components in the presence of the misfire, with computation time reduced by 39%. The algorithm can be easily reapplied, and a new model generated, whenever engine speed or individual cylinder parameters are changed. Copyright © 2008 by ASME. 130

Human embryonic stem (hES) cells have an abbreviated G1 phase of the cell cycle. How cells expedite G1 events that are required for the initiation of S phase has not been resolved. One key regulatory pathway that controls G1/S-phase transition is the cyclin E/CDK2-dependent activation of the coactivator protein nuclear protein, ataxia–telangiectasia locus/histone nuclear factor-P (p220NPAT/HiNF-P) complex that induces histone gene transcription. In this study, we use the subnuclear organization of factors controlling histone gene expression to define mechanistic differences in the G1 phase of hES and somatic cells using in situ immunofluorescence microscopy and fluorescence in situ hybridization (FISH). We show that histone gene expression is supported by the staged assembly and modification of a unique subnuclear structure that coordinates initiation and processing of transcripts originating from histone gene loci. Our results demonstrate that regulatory complexes that mediate transcriptional initiation (e.g., p220NPAT) and 3′-end processing (e.g., Lsm10, Lsm11, and SLBP) of histone gene transcripts colocalize at histone gene loci in dedicated subnuclear foci (histone locus bodies) that are distinct from Cajal bodies. Although appearance of CDK2-phosphorylated p220NPAT in these domains occurs at the time of S-phase entry, histone locus bodies are formed ≈1 to 2 h before S phase in embryonic cells but 6 h before S phase in somatic cells. These temporal differences in the formation of histone locus bodies suggest that the G1 phase of the cell cycle in hES cells is abbreviated in part by contraction of late G1.

This paper proposes a technique to quantitatively and systematically search for decoupling among elements of a dynamic system model, and to partition models in which decoupling is found. The method can validate simplifying assumptions based on decoupling, determine when decoupling breaks down due to changes in system parameters or inputs, and indicate required model changes. A high-fidelity model is first generated using the bond graph formalism. The relative contributions of the terms of the generalized Kirchoff loop and node equations are computed by calculating and comparing a measure of their power flow. Negligible aggregate bond power at a constraint equation node indicates an unnecessary term, which is then removed from the model by replacing the associated bond by a modulated source of generalized effort or flow. If replacement of all low-power bonds creates separate bond graphs that are joined by modulating signals, then the model can be partitioned into driving and driven subsystems. The partitions are smaller than the original model, have lower-dimension design variable vectors, and can be simulated separately or in parallel. The partitioning algorithm can be employed alongside existing automated modeling techniques to facilitate efficient, accurate simulation-based design of dynamic systems. Copyright © 2007 by ASME. 129 503 513 503-513

A dynamic system model is proper for a particular application if it achieves the accuracy required by the application with minimal complexity. Because model complexity often-but not always-correlates inversely with simulation speed, a proper model is often alternatively defined as one balancing accuracy and speed. Such balancing is crucial for applications requiring both model accuracy and speed, such as system optimization and hardware-in-the-loop simulation. Furthermore, the simplicity of proper models conduces to control system analysis and design, particularly given the ease with which lower-order controllers can be implemented compared to higher-order ones. The literature presents many algorithms for deducing proper models from simpler ones or reducing complex models until they become proper. This paper presents a broad survey of the proper modeling literature. To simplify the presentation, the algorithms are classified into frequency, projection, optimization, and energy based, based on the metrics they use for obtaining proper models. The basic mechanics, properties, advantages, and limitations of the methods are discussed, along with the relationships between different techniques, with the intention of helping the modeler to identify the most suitable proper modeling method for a given application. Copyright © 2008 by ASME. 130 610081 6100813 0610081-06100813

Vital to the effectiveness of simulation-based design is having a model of known quality of the system being designed. The purpose of this paper is to validate a simplified dynamic model of an FMTV (Family of Medium Tactical Vehicles) for a range of system parameters using a previously developed technique for determining model robustness and accuracy within a design space. The literature provides an algorithm called AVASIM (Accuracy and Validity Algorithm for Simulation) for assessing model validity systematically and quantitatively. AVASIM assess the validity of a model based on a specific input and set of system parameters. The literature also defines a procedure for evaluating the robustness and accuracy of a model with respect to input and system parameter variations based on the AVASIM algorithm. This procedure produces a Range of Validity for a model that is quantitative, systematic and based on physically meaningful specifications In this paper the Range of Validity techniques are applied to a reduced model of an FMTV in order to verify its accuracy and robustness within a design space. The results from the analysis show that for the design space and simulation conditions chosen a reduced order model of the FMTV vehicle is more than sufficiently accurate. Design decisions can be made with confidence and design optimization studies can be performed faster while using this reduced model. Copyright © 2005 SAE International.

The Milliken Moment Method (MMM) can be used to quantify the constraints imposed on vehicle stability and controllability by front and rear tire traction limitations. The main aspect of the Milliken Moment Method is the plot of vehicle's yaw moment versus lateral acceleration for given vehicle sideslip and steering angle ranges. This plot is typically called the Milliken Moment Diagram (MMD). This paper proposes a dynamic simulation approach to implementing the MMM that emulates the traditional experimental one. The approach embeds a vehicle dynamics model in a control loop that maintains a constant desired sideslip angle, and integrates the resulting controlled vehicle system model in time to generate the MMD. A numerical example demonstrates the approach and shows that the while the proposed approach may not be as efficient as the traditional computer based approach, it has the advantage of being able to used a variety of existing vehicle dynamics models with commonly available numerical simulation packages in order to generate the MMD's. Copyright © 2005 SAE International.

Vital to the effectiveness of simulation-based design is having a system model of known quality. Previous research introduced an algorithm called AVASIM for assessing model validity systematically and quantitatively. AVASIM assess the accuracy and validity of a model based on a specific input and set of system parameters. The purpose of this paper is to present a AVASIM-based methodology that defines a range of validity of a model with respect to input and system parameter variations Two illustrative examples are presented to explore the feasibility of the proposed procedure. The first example analyzes a linearized version of a nonlinear transient vehicle-handling model. This model's accuracy and validity are evaluated with respect to variation of two system parameters, resulting in a two-dimensional range of validity. Then a complex nonlinear hydrogen fuel cell model is linearized in order to investigate its accuracy and validity with respect to two input parameters. This again results in a two-dimensional range of validity, but with respect to input rather than system parameters. The results agree well with what is expected for the various models based on knowledge of the effects of linearization on model accuracy. The proposed algorithm for assessing model range of validity is a promising tool for determining model quality and thus potentially useful for simulation-based design. Copyright © 2004 by ASME. 73 835 843 835-843

Simplified models for predicting engine mount forces have traditionally been developed based on the assumption that for a well-balanced low-speed engine, the reciprocating dynamics can be decoupled from the three-dimensional motion of the engine block. In this paper the simplification is done systematically, using a technique previously developed by the authors to search for decoupling within a model, and to partition models in which decoupling is found. Beginning with a fully-coupled bond graph model of a balanced in-line six-cylinder engine, bonds representing negligible constraint terms are found based on aggregate power flow, and are converted to modulated sources. Separate bond graphs joined by modulating signals result. The "driving" bond graph represents the reciprocating dynamics, and the "driven" bond graph represents motion of the block on its mounts. The partitions are smaller than the original model and are simulated individually to accurately predict the dominant third-order mount forces with significant computational savings. The decoupling is found without the modeler relying on traditional assumed forms of the one-way coupled model, and can be quantitatively tracked as the system parameters and inputs change. Copyright © 2004 by ASME. 73 821 833 821-833

A new generation of machine tools called Reconfigurable Machine Tools (RMTs) is emerging as a means for industry to be more competitive in a market that experiences frequent changes in demand. New methodologies and tools are necessary for the efficient design of these machine tools. It is the purpose of this paper to present a modular approach for RMT servo axis modeling, which is part of a larger effort to develop an integrated RMT design and control environment. The components of the machine tool are modeled in a modular way, such that the model of any given configuration can be obtained by assembling the corresponding component models together based on the topology of the machine. The component models are built using the bond graph language that enables the straightforward development of the required modular library. These machine tool models can be used for the evaluation, design and control of the RMT servo axes. The approach is demonstrated through examples, and the benefits and drawbacks of this approach are discussed. The results show that the proposed approach is a promising step towards an automated and integrated RMT design environment, and the challenges in order to complete this goal are discussed. Copyright © 2004 by ASME. 15 393 399 393-399