Differential roles of the PKC novel isoforms, PKCδ and PKCε, in mouse and human platelets

Background Increasing evidence suggests that individual isoforms of protein kinase C (PKC) play distinct roles in regulating platelet activation. Methodology/Principal Findings In this study, we focus on the role of two novel PKC isoforms, PKCδ and PKCε, in both mouse and human platelets. PKCδ is robustly expressed in human platelets and undergoes transient tyrosine phosphorylation upon stimulation by thrombin or the collagen receptor, GPVI, which becomes sustained in the presence of the pan-PKC inhibitor, Ro 31-8220. In mouse platelets, however, PKCδ undergoes sustained tyrosine phosphorylation upon activation. In contrast the related isoform, PKCε, is expressed at high levels in mouse but not human platelets. There is a marked inhibition in aggregation and dense granule secretion to low concentrations of GPVI agonists in mouse platelets lacking PKCε in contrast to a minor inhibition in response to G protein-coupled receptor agonists. This reduction is mediated by inhibition of tyrosine phosphorylation of the FcRγ-chain and downstream proteins, an effect also observed in wild-type mouse platelets in the presence of a PKC inhibitor. Conclusions These results demonstrate a reciprocal relationship in levels of the novel PKC isoforms δ and ε in human and mouse platelets and a selective role for PKCε in signalling through GPVI.

Examining the relationships between Holocene climate change, hydrology, and human society in Ireland

This thesis explores human-environment interactions during the Mid-Late Holocene in raised bogs in central Ireland. The raised bogs of central Ireland are widely-recognised for their considerable palaeoenvironmental and archaeological resources: research over the past few decades has established the potential for such sites to preserve sensitive records of Holocene climatic variability expressed as changes in bog surface wetness (BSW); meanwhile archaeological investigations over the past century have uncovered hundreds of peatland archaeological features dating from the Neolithic through to the Post-Medieval period including wooden trackways, platforms, and deposits of high-status metalwork. Previous studies have attempted to explore the relationship between records of past environmental change and the occurrence of peatland archaeological sites reaching varying conclusions. More recently, environmentally-deterministic models of human-environment interaction in Irish raised bogs at the regional scale have been explicitly tested leading to the conclusion that there is no relationship between BSW and past human activity. These relationships are examined in more detail on a site-by-site basis in this thesis. To that end, testate amoebae-derived BSW records from nine milled former raised bogs in central Ireland were produced from sites with known and dated archaeological records. Relationships between BSW records and environmental conditions within the study area were explored through both the development of a new central Ireland testate amoebae transfer function and through comparisons between recent BSW records and instrumental weather data. Compilation of BSW records from the nine fossil study sites show evidence both for climate forcing, particularly during 3200-2400 cal BP, as well as considerable inter-site variability. Considerable inter-site variability was also evident in the archaeological records of the same sites. Whilst comparisons between BSW and archaeological records do not show a consistent linear relationship, examination of records on a site-by-site basis were shown to reveal interpretatively important contingent relationships. It is concluded therefore, that future research on human-environment interactions should focus on individual sites and should utilise theoretical approaches from the humanities in order to avoid the twin pitfalls of masking important local patterns of change, and of environmental determinism.

Late Würm and Early-Middle Holocene environmental change and human activities in the Northern Apennines, Italy

An enhanced radiocarbon-dated pollen-stratigraphical record from Rovegno (Liguria, 812m asl), northern Apennines (Italy), has provided a history of vegetation succession from before 17,056-16,621 cal yrs BP to the present day. The record indicates the transition from open Pinus woodland to Artemisia dominated grassland, and finally Juniperus shrubland during the late Würm. This is succeeded by Betula and Pinus woodland, and the expansion of thermophilous taxa, namely Abies, Corylus and Quercus during the Late Würm Lateglacial Interstadial. The ‘Younger Dryas’ is possibly represented by an increase in Betula and Artemisia. During the early Holocene, mixed coniferous-deciduous woodland is dominant with Quercus, as well as Abies, Fagus and Corylus. Fagus woodland becomes established sometime before 6488-6318 cal yrs BP, but never becomes a major component of the woodland cover. Throughout the middle Holocene, Abies woodland fl uctuates, with marked declines between 6488-6318 cal yrs BP and 5287-4835 cal yrs BP, although the cause remains uncertain. Finally, the paper evaluates the application of non-pollen palynomorphs, especially coprophilous fungal spores, at Prato Spilla ‘A’ (Emilia Romagna) and concludes that greater caution must be used when interpreting middle Holocene human activity based upon pollen data alone

Just another case of treaty interpretation? Reconciling humanitarian law and human rights law in the ICJ

This chapter offers a fresh critique of the approach taken by the International Court of Justice to the relationship between humanitarian law and human rights law. In so doing, it seeks to move beyond the intractable debates that have dominated this area, offering an original account of the relationship that is firmly grounded in general international law concepts of treaty interpretation.

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.

Therapeutic potential of computer to cerebral cortex implantable devices

In this article, an overview of some of the latest developments in the field of cerebral cortex to computer interfacing (CCCI) is given. This is posed in the more general context of Brain-Computer Interfaces in order to assess advantages and disadvantages. The emphasis is clearly placed on practical studies that have been undertaken and reported on, as opposed to those speculated, simulated or proposed as future projects. Related areas are discussed briefly only in the context of their contribution to the studies being undertaken. The area of focus is notably the use of invasive implant technology, where a connection is made directly with the cerebral cortex and/or nervous system. Tests and experimentation which do not involve human subjects are invariably carried out a priori to indicate the eventual possibilities before human subjects are themselves involved. Some of the more pertinent animal studies from this area are discussed. The paper goes on to describe human experimentation, in which neural implants have linked the human nervous system bidirectionally with technology and the internet. A view is taken as to the prospects for the future for CCCI, in terms of its broad therapeutic role.

Motor imagery induced EEG patterns in spinal cord injury patients and their impact on Brain-Computer Interface accuracy

OBJECTIVE: Assimilating the diagnosis complete spinal cord injury (SCI) takes time and is not easy, as patients know that there is no 'cure' at the present time. Brain-computer interfaces (BCIs) can facilitate daily living. However, inter-subject variability demands measurements with potential user groups and an understanding of how they differ to healthy users BCIs are more commonly tested with. Thus, a three-class motor imagery (MI) screening (left hand, right hand, feet) was performed with a group of 10 able-bodied and 16 complete spinal-cord-injured people (paraplegics, tetraplegics) with the objective of determining what differences were present between the user groups and how they would impact upon the ability of these user groups to interact with a BCI. APPROACH: Electrophysiological differences between patient groups and healthy users are measured in terms of sensorimotor rhythm deflections from baseline during MI, electroencephalogram microstate scalp maps and strengths of inter-channel phase synchronization. Additionally, using a common spatial pattern algorithm and a linear discriminant analysis classifier, the classification accuracy was calculated and compared between groups. MAIN RESULTS: It is seen that both patient groups (tetraplegic and paraplegic) have some significant differences in event-related desynchronization strengths, exhibit significant increases in synchronization and reach significantly lower accuracies (mean (M) = 66.1%) than the group of healthy subjects (M = 85.1%). SIGNIFICANCE: The results demonstrate significant differences in electrophysiological correlates of motor control between healthy individuals and those individuals who stand to benefit most from BCI technology (individuals with SCI). They highlight the difficulty in directly translating results from healthy subjects to participants with SCI and the challenges that, therefore, arise in providing BCIs to such individuals.

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.

Ventilation rates in schools and pupil’s performance using computerized assessment tests

Research shows that poor indoor air quality (IAQ) in school buildings can cause a reduction in the students’ performance assessed by short-term computer-based tests; whereas good air quality in classrooms can enhance children's concentration and also teachers’ productivity. Investigation of air quality in classrooms helps us to characterise pollutant levels and implement corrective measures. Outdoor pollution, ventilation equipment, furnishings, and human activities affect IAQ. In school classrooms, the occupancy density is high (1.8–2.4 m2/person) compared to offices (10 m2/person). Ventilation systems expend energy and there is a trend to save energy by reducing ventilation rates. We need to establish the minimum acceptable level of fresh air required for the health of the occupants. This paper describes a project, which will aim to investigate the effect of IAQ and ventilation rates on pupils’ performance and health using psychological tests. The aim is to recommend suitable ventilation rates for classrooms and examine the suitability of the air quality guidelines for classrooms. The air quality, ventilation rates and pupils’ performance in classrooms will be evaluated in parallel measurements. In addition, Visual Analogue Scales will be used to assess subjective perception of the classroom environment and SBS symptoms. Pupil performance will be measured with Computerised Assessment Tests (CAT), and Pen and Paper Performance Tasks while physical parameters of the classroom environment will be recorded using an advanced data logging system. A total number of 20 primary schools in the Reading area are expected to participate in the present investigation, and the pupils participating in this study will be within the age group of 9–11 years. On completion of the project, based on the overall data recommendations for suitable ventilation rates for schools will be formulated.

Robot-human interaction - practical experiments with a cyborg

This paper presents results to indicate the potential applications of a direct connection between the human nervous system and a computer network. Actual experimental results obtained from a human subject study are given, with emphasis placed on the direct interaction between the human nervous system and possible extra-sensory input. An brief overview of the general state of neural implants is given, as well as a range of application areas considered. An overall view is also taken as to what may be possible with implant technology as a general purpose human-computer interface for the future.

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.

Generic control interface for networked haptic virtual environments

As Virtual Reality pushes the boundaries of the human computer interface new ways of interaction are emerging. One such technology is the integration of haptic interfaces (force-feedback devices) into virtual environments. This modality offers an improved sense of immersion to that achieved when relying only on audio and visual modalities. The paper introduces some of the technical obstacles such as latency and network traffic that need to be overcome for maintaining a high degree of immersion during haptic tasks. The paper describes the advantages of integrating haptic feedback into systems, and presents some of the technical issues inherent in a networked haptic virtual environment. A generic control interface has been developed to seamlessly mesh with existing networked VR development libraries.

Invasive neural prosthesis for neural signal detection and nerve stimulation

This paper specifically examines the implantation of a microelectrode array into the median nerve of the left arm of a healthy male volunteer. The objective was to establish a bi-directional link between the human nervous system and a computer, via a unique interface module. This is the first time that such a device has been used with a healthy human. The aim of the study was to assess the efficacy, compatibility, and long term operability of the neural implant in allowing the subject to perceive feedback stimulation and for neural activity to be detected and processed such that the subject could interact with remote technologies. A case study demonstrating real-time control of an instrumented prosthetic hand by means of the bi-directional link is given. The implantation did not result in infection, and scanning electron microscope images of the implant post extraction have not indicated significant rejection of the implant by the body. No perceivable loss of hand sensation or motion control was experienced by the subject while the implant was in place, and further testing of the subject following the removal of the implant has not indicated any measurable long term defects. The implant was extracted after 96 days. Copyright © 2004 John Wiley & Sons, Ltd.