Competitive endothelial adhesion between Plasmodium falciparum isolates under physiological flow conditions

<p>Abstract</p> <p>Background</p> <p>Sequestration of parasitized red blood cells in the microvasculature of major organs involves a sequence of events that is believed to contribute to the pathogenesis of severe falciparum malaria. <it>Plasmodium falciparum </it>infections are commonly composed of multiple subpopulations of parasites with varied adhesive properties. A key question is: do these subpopulations compete for adhesion to endothelium? This study investigated whether, in a laboratory model of cytoadherence, there is competition in binding to endothelium between pRBC infected with <it>P. falciparum </it>of variant adhesive phenotypes, particularly under flow conditions.</p> <p>Methods</p> <p>Four different <it>P. falciparum </it>isolates, of known adherence phenotypes, were matched in pairs, mixed in different proportions and allowed to bind to cultured human endothelium. Using <it>in vitro </it>competitive static and flow-based adhesion assays, that allow simultaneous testing of the adhesive properties of two different parasite lines, adherence levels of paired <it>P. falciparum </it>isolates were quantified and analysed using either non-parametric Wilcoxon's paired signed rank test or Student paired test.</p> <p>Results</p> <p>Study findings show that <it>P. falciparum </it>parasite lines show marked differences in the efficiency of adhesion to endothelium.</p> <p>Conclusion</p> <p><it>Plasmodium falciparum </it>variants will compete for adhesion to endothelia and variants can be ranked by their efficiency of binding. These findings suggest that variants from a mixed infection will not show uniform cytoadherence and so may vary in their ability to cause disease.</p

Cross-layer enhancement of error control techniques for adaptation layers of DVB satellites

This paper assesses the way error control is managed jointly by Forward Error Codes (FEC) and Cyclic Redundancy Checks (CRC) in the lower layers of today’s Digital Video Broadcasting (DVB) satellites. Mathematical and simulation results clearly show that the outer block codes of the coding schemes used in DVB-S and DVB-S2 (Reed-Solomon and Bose-Chaudhuri-Hocquenghem, respectively) can provide very accurate error-detection information to the receiver in addition to their basic correction task at virtually no cost, making an uncorrected error after decoding an extremely improbable event. For this reason, the workload of CRCs can be ensured safely by the FEC subsystem if a dedicated function allowing the physical layer to share its decoding information with the adaptation layer is set. This particular crosslayer mechanism would allow freeing up the bandwidth currently used by CRCs -which adds up to 10 % for more than 35 % of the total number of IP packets- and pave the way for an enhanced transport of IP over DVB-S2

C-tactile afferent stimulating touch carries a positive affective value

The rewarding sensation of touch in affiliative interactions is hypothesized to be underpinned by a specialized system of nerve fibers called C-Tactile afferents (CTs), which respond optimally to slowly moving, gentle touch, typical of a caress. However, empirical evidence to support the theory that CTs encode socially relevant, rewarding tactile information in humans is currently limited. While in healthy participants, touch applied at CT optimal velocities (1-10cm/sec) is reliably rated as subjectively pleasant, neuronopathy patients lacking large myelinated afferents, but with intact C-fibres, report that the conscious sensation elicited by stimulation of CTs is rather vague. Given this weak perceptual impact the value of self-report measures for assessing the specific affective value of CT activating touch appears limited. Therefore, we combined subjective ratings of touch pleasantness with implicit measures of affective state (facial electromyography) and autonomic arousal (heart rate) to determine whether CT activation carries a positive affective value. We recorded the activity of two key emotion-relevant facial muscle sites (zygomaticus major—smile muscle, positive affect & corrugator supercilii—frown muscle, negative affect) while participants evaluated the pleasantness of experimenter administered stroking touch, delivered using a soft brush, at two velocities (CT optimal 3cm/sec & CT non-optimal 30cm/sec), on two skin sites (CT innervated forearm & non-CT innervated palm). On both sites, 3cm/sec stroking touch was rated as more pleasant and produced greater heart rate deceleration than 30cm/sec stimulation. However, neither self-report ratings nor heart rate responses discriminated stimulation on the CT innervated arm from stroking of the non-CT innervated palm. In contrast, significantly greater activation of the zygomaticus major (smiling muscle) was seen specifically to CT optimal, 3cm/sec, stroking on the forearm in comparison to all other stimuli. These results offer the first empirical evidence in humans that tactile stimulation that optimally activates CTs carries a positive affective valence that can be measured implicitly

Heterologous expression of a novel drug transporter from the malaria parasite alters resistance to quinoline antimalarials

Antimalarial drug resistance hampers effective malaria treatment. Critical SNPs in a particular, putative amino acid transporter were recently linked to chloroquine (CQ) resistance in malaria parasites. Here, we show that this conserved protein (PF3D7_0629500 in Plasmodium falciparum; AAT1 in P. chabaudi) is a structural homologue of the yeast amino acid transporter Tat2p, which is known to mediate quinine uptake and toxicity. Heterologous expression of PF3D7_0629500 in yeast produced CQ hypersensitivity, coincident with increased CQ uptake. PF3D7_0629500-expressing cultures were also sensitized to related antimalarials; amodiaquine, mefloquine and particularly quinine. Drug sensitivity was reversed by introducing a SNP linked to CQ resistance in the parasite. Like Tat2p, PF3D7_0629500-dependent quinine hypersensitivity was suppressible with tryptophan, consistent with a common transport mechanism. A four-fold increase in quinine uptake by PF3D7_0629500 expressing cells was abolished by the resistance SNP. The parasite protein localised primarily to the yeast plasma membrane. Its expression varied between cells and this heterogeneity was used to show that high-expressing cell subpopulations were the most drug sensitive. The results reveal that the PF3D7_0629500 protein can determine the level of sensitivity to several major quinine-related antimalarials through an amino acid-inhibitable drug transport function. The potential clinical relevance is discussed

Specific Receptor Usage in Plasmodium falciparum Cytoadherence Is Associated with Disease Outcome

Our understanding of the basis of severe disease in malaria is incomplete. It is clear that pathology is in part related to the pro-inflammatory nature of the host response but a number of other factors are also thought to be involved, including the interaction between infected erythrocytes and endothelium. This is a complex system involving several host receptors and a major parasite-derived variant antigen (PfEMP1) expressed on the surface of the infected erythrocyte membrane. Previous studies have suggested a role for ICAM-1 in the pathology of cerebral malaria, although these have been inconclusive. In this study we have examined the cytoadherence patterns of 101 patient isolates from varying clinical syndromes to CD36 and ICAM-1, and have used variant ICAM-1 proteins to further characterise this adhesive phenotype. Our results show that increased binding to CD36 is associated with uncomplicated malaria while ICAM-1 adhesion is raised in parasites from cerebral malaria cases

Developmental perspectives on interpersonal affective touch

In the last decade, philosophy, neuroscience and psychology alike have paid increasing attention to the study of interpersonal affective touch, which refers to the emotional and motivational facets of tactile sensation. Some aspects of affective touch have been linked to a neurophysiologically specialised system, namely the C tactile (CT) system. While the role of this sys-tem for affiliation, social bonding and communication of emotions have been widely investigated, only recently researchers have started to focus on the potential role of interpersonal affective touch in acquiring awareness of the body as our own, i.e. as belonging to our psychological ‘self’. We review and discuss recent developmental and adult findings, pointing to the central role of interpersonal affective touch in body awareness and social cognition in health and disorders. We propose that interpersonal affective touch, as an interoceptive modality invested of a social nature, can uniquely contribute to the ongoing debate in philosophy about the primacy of the relational nature of the minimal self

A Rescorla-Wagner Drift-Diffusion Model of Conditioning and Timing

Computational models of classical conditioning have made significant contributions to the theoretic understanding of associative learning, yet they still struggle when the temporal aspects of conditioning are taken into account. Interval timing models have contributed a rich variety of time representations and provided accurate predictions for the timing of responses, but they usually have little to say about associative learning. In this article we present a unified model of conditioning and timing that is based on the influential Rescorla-Wagner conditioning model and the more recently developed Timing Drift-Diffusion model. We test the model by simulating 10 experimental phenomena and show that it can provide an adequate account for 8, and a partial account for the other 2. We argue that the model can account for more phenomena in the chosen set than these other similar in scope models: CSC-TD, MS-TD, Learning to Time and Modular Theory. A comparison and analysis of the mechanisms in these models is provided, with a focus on the types of time representation and associative learning rule used

Taking two to tango:fMRI analysis of improvised joint action with physical contact

<div><p>Many forms of joint action involve physical coupling between the participants, such as when moving a sofa together or dancing a tango. We report the results of a novel two-person functional MRI study in which trained couple dancers engaged in bimanual contact with an experimenter standing next to the bore of the magnet, and in which the two alternated between being the leader and the follower of joint improvised movements. Leading showed a general pattern of self-orientation, being associated with brain areas involved in motor planning, navigation, sequencing, action monitoring, and error correction. In contrast, following showed a far more sensory, externally-oriented pattern, revealing areas involved in somatosensation, proprioception, motion tracking, social cognition, and outcome monitoring. We also had participants perform a “mutual” condition in which the movement patterns were pre-learned and the roles were symmetric, thereby minimizing any tendency toward either leading or following. The mutual condition showed greater activity in brain areas involved in mentalizing and social reward than did leading or following. Finally, the analysis of improvisation revealed the dual importance of motor-planning and working-memory areas. We discuss these results in terms of theories of both joint action and improvisation.</p></div

Business Ethics: The Promise of Neuroscience

Recent advances in cognitive neuroscience research portend well for furthering understanding of many of the fundamental questions in the field of business ethics, both normative and empirical. This article provides an overview of neuroscience methodology and brain structures, and explores the areas in which neuroscience research has contributed findings of value to business ethics, as well as suggesting areas for future research. Neuroscience research is especially capable of providing insight into individual reactions to ethical issues, while also raising challenging normative questions about the nature of moral responsibility, autonomy, intent, and free will. This article also provides a brief summary of the papers included in this special issue, attesting to the richness of scholarly inquiry linking neuroscience and business ethics. We conclude that neuroscience offers considerable promise to the field of business ethics, but we caution against overpromise