Molecule modeling of human pentameric alpha(7) neuronal nicotinic acetylcholine receptor and its interaction with its agonist and competitive antagonist

The nicotinic Acetylcholine Receptor (nAChR) is the major class of neurotransmitter receptors that is involved in many neurodegenerative conditions such as schizophrenia, Alzheimer's and Parkinson's diseases. The N-terminal region or Ligand Binding Domain (LBD) of nAChR is located at pre- and post-synaptic nervous system, which mediates synaptic transmission. nAChR acts as the drug target for agonist and competitive antagonist molecules that modulate signal transmission at the nerve terminals. Based on Acetylcholine Binding Protein (AChBP) from Lymnea stagnalis as the structural template, the homology modeling approach was carried out to build three dimensional model of the N-terminal region of human alpha(7)nAChR. This theoretical model is an assembly of five alpha(7) subunits with 5 fold axis symmetry, constituting a channel, with the binding picket present at the interface region of the subunits. alpha-netlrotoxin is a potent nAChR competitive antagonist that readily blocks the channel resulting in paralysis. The molecular interaction of alpha-Bungarotoxin, a long chain alpha-neurotoxin from (Bungarus multicinctus) and human alpha(7)nAChR seas studied. Agonists such as acetylcholine, nicotine, which are used in it diverse array of biological activities, such as enhancements of cognitive performances, were also docked with the theoretical model of human alpha(7)nAChR. These docked complexes were analyzed further for identifying the crucial residues involved in interaction. These results provide the details of interaction of agonists and competitive antagonists with three dimensional model of the N-terminal region of human alpha(7)nAChR and thereby point to the design of novel lead compounds.

Agonist-selective, receptor-specific interaction of human P-2Y receptors with beta-arrestin-1 and-2

Interaction of G-protein-coupled receptors with beta-arrestins is an important step in receptor desensitization and in triggering "alternative" signals. By means of confocal microscopy and fluorescence resonance energy transfer, we have investigated the internalization of the human P2Y receptors 1, 2, 4, 6, 11, and 12 and their interaction with beta-arrestin-1 and -2. Co-transfection of each individual P2Y receptor with beta-arrestin-1-GFP or beta-arrestin-2-YFP into HEK-293 cells and stimulation with the corresponding agonists resulted in a receptor-specific interaction pattern. The P2Y(1) receptor stimulated with ADP strongly translocated beta-arrestin-2-YFP, whereas only a slight translocation was observed for beta-arrestin-1-GFP. The P2Y(4) receptor exhibited equally strong translocation for beta-arrestin-1-GFP and beta-arrestin-2YFP when stimulated with UTP. The P2Y(6), P2Y(11), and P2Y(12) receptor internalized only when GRK2 was additionally cotransfected, but beta-arrestin translocation was only visible for the P2Y(6) and P2Y(11) receptor. The P2Y(2) receptor showed a beta-arrestin translocation pattern that was dependent on the agonist used for stimulation. UTP translocated beta-arrestin-1-GFP and beta-arrestin-2-YFP equally well, whereas ATP translocated beta-arrestin-1-GFP to a much lower extent than beta-arrestin2- YFP. The same agonist-dependent pattern was seen in fluorescence resonance energy transfer experiments between the fluorescently labeled P2Y(2) receptor and beta-arrestins. Thus, the P2Y(2) receptor would be classified as a class A receptor when stimulated with ATP or as a class B receptor when stimulated with UTP. The ligand-specific recruitment of beta-arrestins by ATP and UTP stimulation of P2Y(2) receptors was further found to result in differential stimulation of ERK phosphorylation. This suggests that the two different agonists induce distinct active states of this receptor that show differential interactions with beta-arrestins.

High bandwidth, large workspace haptic interaction: flying phantoms

It is well understood that for haptic interaction: free motion performance and closed-loop constrained motion performance have conflicting requirements. The difficulties for both conditions are compounded when increased workspace is required as most solutions result in a reduction of achievable impedance and bandwidth. A method of chaining devices together to increase workspace without adverse effect on performance is described and analysed. The method is then applied to a prototype, colloquially known as 'The Flying Phantom', and shown to provide high-bandwidth, low impedance interaction over the full range of horizontal movement across the front of a human user.

Human-machine symbiosis overview

The interface between humans and technology is a rapidly changing field. In particular as technological methods have improved dramatically so interaction has become possible that could only be speculated about even a decade earlier. This interaction can though take on a wide range of forms. Indeed standard buttons and dials with televisual feedback are perhaps a common example. But now virtual reality systems, wearable computers and most of all, implant technology are throwing up a completely new concept, namely a symbiosis of human and machine. No longer is it sensible simply to consider how a human interacts with a machine, but rather how the human-machine symbiotic combination interacts with the outside world. In this paper we take a look at some of the recent approaches, putting implant technology in context. We also consider some specific practical examples which may well alter the way we look at this symbiosis in the future. The main area of interest as far as symbiotic studies are concerned is clearly the use of implant technology, particularly where a connection is made between technology and the human brain and/or nervous system. Often pilot tests and experimentation has been carried out apriori to investigate the eventual possibilities before human subjects are themselves involved. Some of the more pertinent animal studies are discussed briefly here. The paper however concentrates on human experimentation, in particular that carried out by the authors themselves, firstly to indicate what possibilities exist as of now with available technology, but perhaps more importantly to also show what might be possible with such technology in the future and how this may well have extensive social effects. The driving force behind the integration of technology with humans on a neural level has historically been to restore lost functionality in individuals who have suffered neurological trauma such as spinal cord damage, or who suffer from a debilitating disease such as lateral amyotrophic sclerosis. Very few would argue against the development of implants to enable such people to control their environment, or some aspect of their own body functions. Indeed this technology in the short term has applications for amelioration of symptoms for the physically impaired, such as alternative senses being bestowed on a blind or deaf individual. However the issue becomes distinctly more complex when it is proposed that such technology be used on those with no medical need, but instead who wish to enhance and augment their own bodies, particularly in terms of their mental attributes. These issues are discussed here in the light of practical experimental test results and their ethical consequences.

3D path planning with novel multiple 2D layered approach for complex human-robot interaction

Navigating cluttered indoor environments is a difficult problem in indoor service robotics. The Acroboter concept, a novel approach to indoor locomotion, represents unique opportunity to avoid obstacles in indoor environments by navigating the ceiling plane. This mode of locomotion requires the ability to accurately detect obstacles, and plan 3D trajectories through the environment. This paper presents the development of a resilient object tracking system, as well as a novel approach to generating 3D paths suitable for such robot configurations. Distributed human-machine interfacing allowing simulation previewing of actions is also considered in the developed system architecture.

Interaction of visual and haptic information in simulated environments: texture perception

This paper describes experiments relating to the perception of the roughness of simulated surfaces via the haptic and visual senses. Subjects used a magnitude estimation technique to judge the roughness of “virtual gratings” presented via a PHANToM haptic interface device, and a standard visual display unit. It was shown that under haptic perception, subjects tended to perceive roughness as decreasing with increased grating period, though this relationship was not always statistically significant. Under visual exploration, the exact relationship between spatial period and perceived roughness was less well defined, though linear regressions provided a reliable approximation to individual subjects’ estimates.

Human-computer cooperative teleoperation with time delay

Presents a method for model based bilateral control of master-slave arm with time delay between master and slave arms, where the system supports cooperative action between manual and automatic modes. The method realises efficiencies in master-slave arm control with the simplicities of a computer and the flexibility of a skilled human operator.

Investigating familiar interfaces to help older adults learn computer applications more easily

Many older adults wish to gain competence in using a computer, but many application interfaces are perceived as complex and difficult to use, deterring potential users from investing the time to learn them. Hence, this study looks at the potential of ‘familiar’ interface design which builds upon users’ knowledge of real world interactions, and applies existing skills to a new domain. Tools are provided in the form of familiar visual objects, and manipulated like real-world counterparts, rather than with buttons, icons and menus found in classic WIMP interfaces. This paper describes the formative evaluation of computer interactions that are based upon familiar real world tasks, which supports multitouch interaction, involves few buttons and icons, no menus, no right-clicks or double-clicks and no dialogs. Using an example of an email client to test the principles of using “familiarity”, the initial feedback was very encouraging, with 3 of the 4 participants being able to undertake some of the basic email tasks with no prior training and little or no help. The feedback has informed a number of refinements of the design principles, such as providing clearer affordance for visual objects. A full study is currently underway.

Experiments into biology-technology interaction

In this paper a look is taken at how the use of implant and electrode technology can be employed to create biological brains for robots, to enable human enhancement and to diminish the effects of certain neural illnesses. In all cases the end result is to increase the range of abilities of the recipients. An indication is given of a number of areas in which such technology has already had a profound effect, a key element being the need for a clear interface linking a biological brain directly with computer technology. The emphasis is placed on practical scientific studies that have been and are being undertaken and reported on. The area of focus is the use of electrode technology, where either a connection is made directly with the cerebral cortex and/or nervous system or where implants into the human body are involved. The paper also considers robots that have biological brains in which human neurons can be employed as the sole thinking machine for a real world robot body.

Human enhancement: could you become infected with a computer virus?

Experiments demonstrating human enhancement through the implantation of technology in healthy humans have been performed for over a decade by some academic research groups. More recently, technology enthusiasts have begun to realize the potential of implantable technology such as glass capsule RFID transponders. In this paper it is argued that implantable RFID devices have evolved to the point whereby we should consider the devices themselves as simple computers. Presented here is the infection with a computer virus of an RFID device implanted in a human. Coupled with our developing concept of what constitutes the human body and its boundaries, it is argued that this study has given rise to the world’s first human infected with a computer virus. It has taken the wider academic community some time to agree that meaningful discourse on the topic of implantable technology is of value. As developments in medical technologies point to greater possibilities for enhancement, this shift in thinking is not too soon in coming.

Interaction of anthocyanins with human serum albumin: influence of pH and chemical structure on binding

The affinity of anthocyanins for human serum albumin (HSA) was determined by a fluorescence quenching method. The effects of pH and structure of anthocyanins on the binding constants were studied. The constants for binding of anthocyanins to HSA ranged from 1.08 x 10^5 M-1 to 13.16 x 10^5 M-1. A hydrophobic effect at acidic pH was shown by the relatively high positive entropy values under the conditions studied. Electrostatic interactions including hydrogen bonding contributed to the binding at pH 7.4. The effect of structure of anthocyanins on the affinity was pH dependent, particularly the effect of additional hydroxyl substituents. Hydroxyl substituents and glycosylation of anthocyanins decreased the affinity for binding to HSA at lower pH (especially pH 4), but increased the strength of binding at pH 7.4. In contrast, methylation of a hydroxyl group enhanced the binding at acidic pH, while this substitution reduced the strength of binding at pH 7.4. This paper has shown that changes in anthocyanin structure or reductions in pH, which may occur in the region of inflammatory sites, have an effect of the binding of anthocyanins to HSA.