The failure of the health service to meet the needs of looked after children is further emphasised in the following article. Here, Mary Mather, Jane Humphrey and Jenny Robson argue that, despite specific health legislation and the considerable resources which have been allocated for this group over the years, there are a number of elements hindering the system. They identify these by first analysing the medical examinations of looked after children, carried out in one London borough over a two-year period. This analysis is followed by a review of key findings from a survey and series of group discussions with young people, aimed at establishing concerns and priorities from the point of view of themselves as ‘consumers’.

Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3β or stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites, high-resolution native mass spectrometry to measure the degree of phosphorylation, and super-resolution microscopy and electron microscopy to characterize the morphology of aggregates formed. Functionally, compared with the unmodified aggregates, which require heparin induction to assemble, these self-assembled hyperphosphorylated tau aggregates more efficiently disrupt membrane bilayers and induce Toll-like receptor 4-dependent responses in human macrophages. Together, our results demonstrate that hyperphosphorylated tau aggregates are potentially damaging to cells, suggesting a mechanism for how hyperphosphorylation could drive neuroinflammation in tauopathies.

T cells use finger-like protrusions called ‘microvilli’ to interrogate their targets, but why they do so is unknown. To form contacts, T cells must overcome the highly charged, barrier-like layer of large molecules forming a target cell’s glycocalyx. Here, T cells are observed to use microvilli to breach a model glycocalyx barrier, forming numerous small (<0.5 μm diameter) contacts each of which is stabilized by the small adhesive protein CD2 expressed by the T cell, and excludes large proteins including CD45, allowing sensitive, antigen dependent TCR signaling. In the absence of the glycocalyx or when microvillar contact-size is increased by enhancing CD2 expression, strong signaling occurs that is no longer antigen dependent. Our observations suggest that, modulated by the opposing effects of the target cell glycocalyx and small adhesive proteins, the use of microvilli equips T cells with the ability to effect discriminatory receptor signaling.

Much of what we know about the early stages of T cell activation has been obtained from studies of T cells interacting with glass-supported lipid bilayers that favor imaging but are orders of magnitude stiffer than typical cells. We developed a method for attaching lipid bilayers to polydimethylsiloxane polymer supports, producing ''soft bilayers'' with physiological levels of mechanical resistance (Young's modulus of 4 kPa). Comparisons of T cell behavior on soft and glass-supported bilayers revealed that whereas late stages of T cell activation are thought to be substrate-stiffness dependent, early calcium signaling was unaffected by substrate rigidity, implying that early steps in T cell receptor triggering are not mechanosensitive. The exclusion of large receptor-type phosphatases was observed on the soft bilayers, however, even though it is yet to be demonstrated at authentic cell-cell contacts. This work sets the stage for an imaging-based exploration of receptor signaling under conditions closely mimicking physiological cell-cell contact.

animals the full supplement a t a time most conducive to overcoming the acute phase of the deficiency.The present data indicate that vit. B12 is about equally effective by oral or injection administration in promoting growth of young rats on highly specialized depletion diets. The deficiency of vit. Bl2 induced in rats by these rather extreme dietary means does not, therefore, appear to evoke a failure in utilization of the vitamin, but rather a true deficiency and enhanced need for the vitamin itself.The following additions to the diet failed to yield a comparable growth response, and even appeared /to have an inhibitory effect: 510% purified casein, 5-10% of various primary-grown and brewer's yeasts, and additional folic acid. The addition of thymidine, 25-50 mg per kg diet, 4betaine hydrochloride 0.5%) or additional choline 0.1% likewise did not stimulate growth in absence of vit. B12.The growth promoting action of vit. BIZ in rations containing iodinated protein has recently been reviewed.1° Betheil and Lardyll have further compared the effectiveness of vit. BIZ, whole liver substance and extracts high in APA activity, as growth promoting materials for hyperthyroid rats. The ration used by tthese authors was also based on puri-1Q Nutrition Reuiews, 1949, 7: 183. 11 Betheil, J. J., and Lardy, H. A., J . 3--utvition, c 1949, 37, 495.fied casein, 'but did not contain a sulfa drug. I t is worthy of note that mortality is high among our control animals and that death is generalIy preceded by appearance of hemorrhage about the nose and paws. Vit. B12 clearly prevents this syndrome and has a marked effect toward longevity under the dietary conditions imposed.The question of the equivalence of vit. B12 with U.S.P. anti-pernicious anemia units can only be answered by assays in human pernicious anemia patients. Microbiological and animal assays may serve as a useful guide, however, toward this goal. The data presented provide some evidence that concentrated liver extracts which show a. correlation by microbiological assay of 1 U.S.P. unit approximately equal to 1 pg of vit. B12, show a similar approximate equivalence by rat assay. Summary. The growth response of vit. BIZ 'depleted rats under the conditions studied is proportional to the vit. B12 administered in the critical range of .025-.1 pg per rat day. Oral and injection administration of the vitamin at critical levels yield approximately equal growth responses. Addition of the vitamin to the diet, multiple dosing or single dosing the first day of assay also appear roughly equivalent. A preliminary correlation between the results of microbiological and rat assays as applied to injectable liver extracts was obtained.