Interhemispheric Interactions between the Human Primary Somatosensory Cortices

In the somatosensory domain it is still unclear at which processing stage information reaches the opposite hemispheres. Due to dense transcallosal connections, the secondary somatosensory cortex (S2) has been proposed to be the key candidate for interhemispheric information transfer. However, recent animal studies showed that the primary somatosensory cortex (S1) might as well account for interhemispheric information transfer. Using paired median nerve somatosensory evoked potential recordings in humans we tested the hypothesis that interhemispheric inhibitory interactions in the somatosensory system occur already in an early cortical processing stage such as S1. Conditioning right S1 by electrical median nerve (MN) stimulation of the left MN (CS) resulted in a significant reduction of the N20 response in the target (left) S1 relative to a test stimulus (TS) to the right MN alone when the interstimulus interval between CS and TS was between 20 and 25 ms. No such changes were observed for later cortical components such as the N20/P25, N30, P40 and N60 amplitude. Additionally, the subcortically generated P14 response in left S1 was also not affected. These results document the existence of interhemispheric inhibitory interactions between S1 in human subjects in the critical time interval of 20–25 ms after median nerve stimulation

Mirror Symmetric Bimanual Movement Priming Can Increase Corticomotor Excitability and Enhance Motor Learning

Repetitive mirror symmetric bilateral upper limb may be a suitable priming technique for upper limb rehabilitation after stroke. Here we demonstrate neurophysiological and behavioural after-effects in healthy participants after priming with 20 minutes of repetitive active-passive bimanual wrist flexion and extension in a mirror symmetric pattern with respect to the body midline (MIR) compared to an control priming condition with alternating flexion-extension (ALT). Transcranial magnetic stimulation (TMS) indicated that corticomotor excitability (CME) of the passive hemisphere remained elevated compared to baseline for at least 30 minutes after MIR but not ALT, evidenced by an increase in the size of motor evoked potentials in ECR and FCR. Short and long-latency intracortical inhibition (SICI, LICI), short afferent inhibition (SAI) and interhemispheric inhibition (IHI) were also examined using pairs of stimuli. LICI differed between patterns, with less LICI after MIR compared with ALT, and an effect of pattern on IHI, with reduced IHI in passive FCR 15 minutes after MIR compared with ALT and baseline. There was no effect of pattern on SAI or FCR H-reflex. Similarly, SICI remained unchanged after 20 minutes of MIR. We then had participants complete a timed manual dexterity motor learning task with the passive hand during, immediately after, and 24 hours after MIR or control priming. The rate of task completion was faster with MIR priming compared to control conditions. Finally, ECR and FCR MEPs were examined within a pre-movement facilitation paradigm of wrist extension before and after MIR. ECR, but not FCR, MEPs were consistently facilitated before and after MIR, demonstrating no degradation of selective muscle activation. In summary, mirror symmetric active-passive bimanual movement increases CME and can enhance motor learning without degradation of muscle selectivity. These findings rationalise the use of mirror symmetric bimanual movement as a priming modality in post-stroke upper limb rehabilitation

Towards Universal Structure-Based Prediction of Class II MHC Epitopes for Diverse Allotypes

The binding of peptide fragments of antigens to class II MHC proteins is a crucial step in initiating a helper T cell immune response. The discovery of these peptide epitopes is important for understanding the normal immune response and its misregulation in autoimmunity and allergies and also for vaccine design. In spite of their biomedical importance, the high diversity of class II MHC proteins combined with the large number of possible peptide sequences make comprehensive experimental determination of epitopes for all MHC allotypes infeasible. Computational methods can address this need by predicting epitopes for a particular MHC allotype. We present a structure-based method for predicting class II epitopes that combines molecular mechanics docking of a fully flexible peptide into the MHC binding cleft followed by binding affinity prediction using a machine learning classifier trained on interaction energy components calculated from the docking solution. Although the primary advantage of structure-based prediction methods over the commonly employed sequence-based methods is their applicability to essentially any MHC allotype, this has not yet been convincingly demonstrated. In order to test the transferability of the prediction method to different MHC proteins, we trained the scoring method on binding data for DRB1*0101 and used it to make predictions for multiple MHC allotypes with distinct peptide binding specificities including representatives from the other human class II MHC loci, HLA-DP and HLA-DQ, as well as for two murine allotypes. The results showed that the prediction method was able to achieve significant discrimination between epitope and non-epitope peptides for all MHC allotypes examined, based on AUC values in the range 0.632–0.821. We also discuss how accounting for peptide binding in multiple registers to class II MHC largely explains the systematically worse performance of prediction methods for class II MHC compared with those for class I MHC based on quantitative prediction performance estimates for peptide binding to class II MHC in a fixed register

Tracking Antigen-Specific T-Cells during Clinical Tolerance Induction in Humans

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3–5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets

Of Bits and Bugs — On the Use of Bioinformatics and a Bacterial Crystal Structure to Solve a Eukaryotic Repeat-Protein Structure

Pur-α is a nucleic acid-binding protein involved in cell cycle control, transcription, and neuronal function. Initially no prediction of the three-dimensional structure of Pur-α was possible. However, recently we solved the X-ray structure of Pur-α from the fruitfly Drosophila melanogaster and showed that it contains a so-called PUR domain. Here we explain how we exploited bioinformatics tools in combination with X-ray structure determination of a bacterial homolog to obtain diffracting crystals and the high-resolution structure of Drosophila Pur-α. First, we used sensitive methods for remote-homology detection to find three repetitive regions in Pur-α. We realized that our lack of understanding how these repeats interact to form a globular domain was a major problem for crystallization and structure determination. With our information on the repeat motifs we then identified a distant bacterial homolog that contains only one repeat. We determined the bacterial crystal structure and found that two of the repeats interact to form a globular domain. Based on this bacterial structure, we calculated a computational model of the eukaryotic protein. The model allowed us to design a crystallizable fragment and to determine the structure of Drosophila Pur-α. Key for success was the fact that single repeats of the bacterial protein self-assembled into a globular domain, instructing us on the number and boundaries of repeats to be included for crystallization trials with the eukaryotic protein. This study demonstrates that the simpler structural domain arrangement of a distant prokaryotic protein can guide the design of eukaryotic crystallization constructs. Since many eukaryotic proteins contain multiple repeats or repeating domains, this approach might be instructive for structural studies of a range of proteins

How to use the world's scarce selenium resources efficiently to increase the selenium concentration in food

The world's rare selenium resources need to be managed carefully. Selenium is extracted as a by-product of copper mining and there are no deposits that can be mined for selenium alone. Selenium has unique properties as a semi-conductor, making it of special value to industry, but it is also an essential nutrient for humans and animals and may promote plant growth and quality. Selenium deficiency is regarded as a major health problem for 0.5 to 1 billion people worldwide, while an even larger number may consume less selenium than required for optimal protection against cancer, cardiovascular diseases and severe infectious diseases including HIV disease. Efficient recycling of selenium is difficult. Selenium is added in some commercial fertilizers, but only a small proportion is taken up by plants and much of the remainder is lost for future utilization. Large biofortification programmes with selenium added to commercial fertilizers may therefore be a fortification method that is too wasteful to be applied to large areas of our planet. Direct addition of selenium compounds to food (process fortification) can be undertaken by the food industry. If selenomethionine is added directly to food, however, oxidation due to heat processing needs to be avoided. New ways to biofortify food products are needed, and it is generally observed that there is less wastage if selenium is added late in the production chain rather than early. On these bases we have proposed adding selenium-enriched, sprouted cereal grain during food processing as an efficient way to introduce this nutrient into deficient diets. Selenium is a non-renewable resource. There is now an enormous wastage of selenium associated with large-scale mining and industrial processing. We recommend that this must be changed and that much of the selenium that is extracted should be stockpiled for use as a nutrient by future generations