Is LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?

The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described.     

DrawBot: a bio-inspired robotic portraitist

Abstract

We are developing the control architecture of a portraitist artificial agent called DrawBot that reproduces the visuomotor behaviour of a human carrying out a realistic portrait. The visuomotor strategy adopted by DrawBot is based on computational models of eye movements in human beings,and one xperimental findings on eye-hand coordination in expert draughtsmen. In this paper we present a behavioural model of the visuomotor coordination adopted by a draughtsman, designed in terms of visual routines.Eventually we outline the implementation of the basic routines.     

An autonomous educational mobile robot mediator

So far, most of the applications of robotic technology to education have mainly focused on supporting the teaching of subjects that are closely related to the Robotics field, such as robot programming, robot construction, or mechatronics. Moreover, most of the applications have used the robot as an end or a passive tool of the learning activity, where the robot has been constructed or programmed. In this paper, we present a novel application of robotic technologies to education, where we use the real world situatedness of a robot to teach non-robotic related subjects, such as math and physics. Furthermore, we also provide the robot with a suitable degree of autonomy to actively guide and mediate in the development of the educational activity. We present our approach as an educational framework based on a collaborative and constructivist learning environment, where the robot is able to act as an interaction mediator capable of managing the interactions occurring among the working students. We illustrate the use of this framework by a 4-step methodology that is used to implement two educational activities. These activities were tested at local schools with encouraging results. Accordingly, the main contributions of this work are: i) A novel use of a mobile robot to illustrate and teach relevant concepts and properties of the real world; ii) A novel use of robots as mediators that autonomously guide an educational activity using a collaborative and constructivist learning approach; iii) The implementation and testing of these ideas in a real scenario, working with students at local schools.

NURBS-Enhanced Finite Element Method (NEFEM)

The development of NURBS-Enhanced Finite Element Method (NEFEM) is revisited. This technique allows a seamless integration of the CAD boundary representation of the domain and the finite element method (FEM). The importance of the geometrical model in finite element simulations is addressed and the benefits and potential of NEFEM are discussed and compared with respect to other curved finite element techniques.     

Molecular basis of agonicity and antagonicity in the androgen receptor studied by molecular dynamics simulations

Treatment of prostate cancer patients with antiandrogens is initially successful, though the therapy often becomes refractory over the time. This mechanism is not fully understood, but the presence of androgen receptor (AR) mutant forms which are activated by antiandrogens and other endogenous ligands, and overexpression of the receptor have been suggested. In an attempt to explain the molecular basis for agonicity and antagonicity in the androgen receptor, and the changes on biological activity of subtle modifications at the ligand and receptor (mutations) level, molecular dynamics simulations were performed on the androgen receptor wild type (WT), and T877A and W741 mutant forms, complexed with several non-steroidal androgens. The stabilizing role of residues from helices 3, 5, 11 and 12 was observed in non-steroidal androgens R-3, S-1, and R-bicalutamide and hydroxyflutamide in resistant mutations. In the AR WT antiandrogen R-bicalutamide complex, destabilization of M895 by both W741 and the sulfonyl linkage of the ligand may be responsible for reported antagonism. Changes in the ligand or mutations alleviating this effect were observed to stabilize the receptor in the active conformation, thus developing resistance to R-bicalutamide. The results presented provide a plausible explanation for the molecular basis of agonicity and antagonicity in the androgen receptor, and complement previous studies using static crystal structures, incorporating for the first time protein dynamics into the analysis. Thus, our results provide a valuable framework for the structure-based design of improved antiandrogens.     

Programmable logic construction kits for hyper-real-time neuronal modeling

Programmable logic designs are presented that achieve exact integration of leaky integrate-and-fire soma and dynamical synapse neuronal models and incorporate spike-time dependent plasticity and axonal delays. Highly accurate numerical performance has been achieved by modifying simpler forward-Euler-based circuitry requiring minimal circuit allocation, which, as we show, behaves equivalently to exact integration. These designs have been implemented and simulated at the behavioral and physical device levels, demonstrating close agreement with both numerical and analytical results. By exploiting finely grained parallelism and single clock cycle numerical iteration, these designs achieve simulation speeds at least five orders of magnitude faster than the nervous system, termed here hyper-real-time operation, when deployed on commercially available field-programmable gate array (FPGA) devices. Taken together, our designs form a programmable logic construction kit of commonly used neuronal model elements that supports the building of large and complex architectures of spiking neuron networks for real-time neuromorphic implementation, neurophysiological interfacing, or efficient parameter space investigations.     

Output feedback trajectory stabilization of the uncertainty DC servomechanism system

This work proposes a solution for the output feedback trajectory-tracking problem in the case of an uncertain DC servomechanism system. The system consists of a pendulum actuated by a DC motor and subject to a time-varying bounded disturbance. The control law consists of a Proportional Derivative controller and an uncertain estimator that allows compensating the effects of the unknown bounded perturbation. Because the motor velocity state is not available from measurements, a second-order sliding-mode observer permits the estimation of this variable in finite time. This last feature allows applying the Separation Principle. The convergence analysis is carried out by means of the Lyapunov method. Results obtained from numerical simulations and experiments in a laboratory prototype show the performance of the closed loop system.     

Teaching Macroeconomics with GAMS

Our general goal in this paper is to show how to implement in GAMS standard deterministic nonlinear macro models, and stochastic linear macro models with rational expectations. We will also present basic concepts on solution methods and policy analysis for these kinds of models. As a practical illustration, we will use some well known teaching and experimental models in the macroeconomic literature.     

Alzheimer paired helical filaments (PHFs) studied by high-resolution TEM: what can vertical Pt-C replication tell us about the organization of the pronase-digested PHF core?

Untreated paired helical filaments (PHFs) and pronase-digested PHF-core filaments were stereoscopically imaged with a freeze-drying vertical platinum-carbon replication preparation method for TEM. The untreated PHF have an average wide region (W) = 22.8 +/- 2.4 nm, a narrow region (T) = 10.6 +/- 1.7 nm, and a helical turn period (L) = 78.6 +/- 13.4. The surfaces of the untreated PHF's fuzzy coat appears disorganized. The widths of the pronase-treated PHF-core filaments were significantly reduced (W(d) = 14.8 +/- 1.2 nm, T(d) = 5.7 +/- 1.0 nm, and L(d) = 75.4 +/- 17 nm). The surfaces of the untreated PHF contained approximately 1.1 nm strands, the same size as tau monomer ( approximately 1.0 nm). The pronase-digested PHF cores mostly contained approximately 1.6 +/- 0.3 nm strands although strand diameters ranged from 0.6-2.5 nm. The strands sometimes appear to be wrapped around the filament axis; less often, they appear to be roughly parallel to the PHF axis, and otherwise appear to be randomly oriented. Images of pronase-digested PHF core images are discussed in relation to the core's biochemical composition, its proposed beta structure, and structural subunit models. Images of the untreated and the pronase-digested PHF support a helical ribbon morphology.