Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.

SummaryThe practice of anaesthesia was revolutionised by the ideas of Archie Brain. The routine use of a facemask to manage the airway was not a hands-free technique, despite the development of various harnesses, and made adequate record-keeping difficult. The tracheal tube was associated with some morbidity, which some felt was unsuitable for day surgery. Brain developed an airway management device that was less stressful to the patient than tracheal intubation, and was, however, as safe as using a facemask and airway. Brain also hoped his device would function for cases where mask ventilation was particularly difficult and thus give anaesthetists a safer alternative to a complex intubation, especially in emergency scenarios.

SummaryFour observers estimated the weight and height of 38 patients who were lying covered on operating theatre trolleys. Regression analysis of the results was performed for each observer. The results showed marked variation in ability to assess these characteristics accurately.

Metal-catalysed exchange has been used extensively in the laboratories of AstraZeneca plc at R&D Charnwood to label a variety of molecules of pharmaceutical interest with the isotopes of deuterium and tritium. Despite early prejudices against the use of tritiated compounds, particularly in ADME studies, the development of directed isotopic exchange techniques has enabled timely and economic support for many pharmaceutical projects.