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We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated KV1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to KV1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for KV1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. PET-CT imaging with 18F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. In keeping with its arthrotropism, EgK5 treats disease in a rat model of rheumatoid arthritis. It was also effective in treating disease in a rat model of atopic dermatitis. No signs of toxicity are observed at 10-100 times the in vivo dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7(-) effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases.

Drilling of fiber-reinforced plastics (FRP's) is an inevitable machining operation, because it facilitates assembly of several components by means of mechanical fastening. But, drilling of FRP leads to delamination which results in reduced life and efficiency of the FRP part. The delamination that induced during drilling is directly affected by the thrust force and torque. In the present research endeavour, four different types of drill point geometries have been used for making of holes in two different types of composite laminates. The drilling of composite laminate has been conducted at three different levels of spindle speed and feed rate. A new artificial neural network (ANN) approach has been proposed to predict the drilling-induced thrust force and torque. The values of thrust force and torque predicted by the proposed ANN models are in close agreement with the experimental values.

This paper discusses the issues involved in calculating indices of composite reliability for "modular" or "unitised" assessments of the kind used in GCSEs, AS and A level examinations in England. The increasingly widespread use of on-screen marking has meant that the item-level data required for calculating indices of reliability is now routinely available for most (but not all) units of unitised assessments. Whilst it is relatively straightforward to obtain indices of reliability at unit level, it is far more complex to obtain indices at overall assessment level because of problems created by: (i) the number of different possible "routes" to the final assessment; (ii) the different knowledge, skills and understanding assessed in different units; (iii) the wide variety in item type and size within and across units; (iv) the fact that the item-level data required for calculating reliability indices is not available (or does not exist) for certain units and (v) the different intended weighting of different units in the composite total and the possible distortion of these weights by use of the Uniform Mark Scale. We derive and compare several indices of composite reliability for, as an example, a three-unit assessment using both classical test theory and item response theory. We conclude that while it is desirable to derive and report indices of reliability at unit level, it is less appropriate at the level of the whole assessment. (Contains 6 tables, 1 figure, and 2 notes.)