Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition

The DNA Damage Response (DDR) pathway represents a signalling mechanism that is activated in eukaryotic cells following DNA damage and comprises of proteins involved in DNA damage detection, DNA repair, cell cycle arrest and apoptosis. This pathway consists of an intricate network of signalling interactions driving the cellular ability to recognise DNA damage and recruit specialised proteins to take decisions between DNA repair or apoptosis. ATM and ATR are central components of the DDR pathway. The activities of these kinases are vital in DNA damage induced phosphorylational induction of DDR substrates. Here, firstly we have experimentally determined DDR signalling network surrounding the ATM/ATR pathway induced following double stranded DNA damage by monitoring and quantifying time dependent inductions of their phosphorylated forms and their key substrates. We next involved an automated inference of unsupervised predictive models of time series data to generate in silico (molecular) interaction maps. We characterized the complex signalling network through system analysis and gradual utilisation of small time series measurements of key substrates through a novel network inference algorithm. Furthermore, we demonstrate an application of an assumption-free reverse engineering of the intricate signalling network of the activated ATM/ATR pathway. We next studied the consequences of such drug induced inductions as well as of time dependent ATM kinase inhibition on cell survival through further biological experiments. Intermediate and temporal modelling outcomes revealed the distinct signaling profile associated with ATM kinase activity and inhibition and explained the underlying signalling mechanism for dual ATM functionality in cytotoxic and cytoprotective pathways

Time integration and steady-state continuation for 2d lubrication equations

Lubrication equations allow to describe many structurin processes of thin liquid films. We develop and apply numerical tools suitable for their analysis employing a dynamical systems approach. In particular, we present a time integration algorithm based on exponential propagation and an algorithm for steady-state continuation. In both algorithms a Cayley transform is employed to overcome numerical problems resulting from scale separation in space and time. An adaptive time-step allows to study the dynamics close to hetero- or homoclinic connections. The developed framework is employed on the one hand to analyse different phases of the dewetting of a liquid film on a horizontal homogeneous substrate. On the other hand, we consider the depinning of drops pinned by a wettability defect. Time-stepping and path-following are used in both cases to analyse steady-state solutions and their bifurcations as well as dynamic processes on short and long time-scales. Both examples are treated for two- and three-dimensional physical settings and prove that the developed algorithms are reliable and efficient for 1d and 2d lubrication equations, respectively.Comment: 33 pages, 16 figure

Kinematic Performance Measures and Optimization of Parallel Kinematics Manipulators: A Brief Review

This chapter covers a number of kinematic performance indices that are instrumental in designing parallel kinematics manipulators. These indices can be used selectively based on manipulator requirements and functionality. This would provide the very practical tool for designers to approach their needs in a very comprehensive fashion. Nevertheless, most applications require a more composite set of requirements that makes optimizing performance more challenging. The later part of this chapter will discuss single-objective and multi-objectives optimization that could handle certain performance indices or a combination of them. A brief description of most common techniques in the literature will be provided

Parallel Manipulators

In recent years, parallel kinematics mechanisms have attracted a lot of attention from the academic and industrial communities due to potential applications not only as robot manipulators but also as machine tools. Generally, the criteria used to compare the performance of traditional serial robots and parallel robots are the workspace, the ratio between the payload and the robot mass, accuracy, and dynamic behaviour. In addition to the reduced coupling effect between joints, parallel robots bring the benefits of much higher payload-robot mass ratios, superior accuracy and greater stiffness; qualities which lead to better dynamic performance. The main drawback with parallel robots is the relatively small workspace. A great deal of research on parallel robots has been carried out worldwide, and a large number of parallel mechanism systems have been built for various applications, such as remote handling, machine tools, medical robots, simulators, micro-robots, and humanoid robots. This book opens a window to exceptional research and development work on parallel mechanisms contributed by authors from around the world. Through this window the reader can get a good view of current parallel robot research and applications

Kinematic calibration of Orthoglide-type mechanisms from observation of parallel leg motions

The paper proposes a new calibration method for parallel manipulators that allows efficient identification of the joint offsets using observations of the manipulator leg parallelism with respect to the base surface. The method employs a simple and low-cost measuring system, which evaluates deviation of the leg location during motions that are assumed to preserve the leg parallelism for the nominal values of the manipulator parameters. Using the measured deviations, the developed algorithm estimates the joint offsets that are treated as the most essential parameters to be identified. The validity of the proposed calibration method and efficiency of the developed numerical algorithms are confirmed by experimental results. The sensitivity of the measurement methods and the calibration accuracy are also studied

Modeling parallel robot kinematics for 3T2R and 3T3R tasks using reciprocal sets of Euler angles

Industrial manipulators and parallel robots are often used for tasks, such as drilling or milling, that require three translational, but only two rotational degrees of freedom ("3T2R"). While kinematic models for specific mechanisms for these tasks exist, a general kinematic model for parallel robots is still missing. This paper presents the definition of the rotational component of kinematic constraints equations for parallel robots based on two reciprocal sets of Euler angles for the end-effector orientation and the orientation residual. The method allows completely removing the redundant coordinate in 3T2R tasks and to solve the inverse kinematics for general serial and parallel robots with the gradient descent algorithm. The functional redundancy of robots with full mobility is exploited using nullspace projection

Pressure-Constrained, Reduced-DOF, Interconnected Parallel Manipulators with Applications to Space Suit Design

This dissertation presents the concept of a Morphing Upper Torso, an innovative pressure suit design that incorporates robotic elements to enable a resizable, highly mobile and easy to don/doff spacesuit. The torso is modeled as a system of interconnected, pressure-constrained, reduced-DOF, wire-actuated parallel manipulators, that enable the dimensions of the suit to be reconfigured to match the wearer. The kinematics, dynamics and control of wire-actuated manipulators are derived and simulated, along with the Jacobian transforms, which relate the total twist vector of the system to the vector of actuator velocities. Tools are developed that allow calculation of the workspace for both single and interconnected reduced-DOF robots of this type, using knowledge of the link lengths. The forward kinematics and statics equations are combined and solved to produce the pose of the platforms along with the link tensions. These tools allow analysis of the full Morphing Upper Torso design, in which the back hatch of a rear-entry torso is interconnected with the waist ring, helmet ring and two scye bearings. Half-scale and full-scale experimental models are used along with analytical models to examine the feasibility of this novel space suit concept. The analytical and experimental results demonstrate that the torso could be expanded to facilitate donning and doffing, and then contracted to match different wearer's body dimensions. Using the system of interconnected parallel manipulators, suit components can be accurately repositioned to different desired configurations. The demonstrated feasibility of the Morphing Upper Torso concept makes it an exciting candidate for inclusion in a future planetary suit architecture