Integrin interactions with extracellular matrix proteins are mediated by brief oligopeptide recognition sequences, and synthetic peptides containing such sequences can inhibit integrin binding to the matrix. The RGD peptide motif is recognized by many integrins including ␣v␤6, a specific receptor for fibronectin thought to support epithelial cell proliferation during wound healing and carcinoma progression. We report here the discovery of an unexpected non-RGD recognition motif for integrin ␣v␤6. We compared the recognition profiles of recombinant ␣v␤6 and ␣v␤3 integrins by using phage display screening employing 7-mer and 12-mer peptide libraries. As predicted, phages binding strongly to ␣v␤3 contained ubiquitous RGD sequences. However, on ␣v␤6, in addition to RGD-containing phages, one-quarter of the population from the 12-mer library contained the distinctive consensus motif DLXXL. A synthetic DLXXL peptide, RTDLDSLRTYTL, selected from the phage sequences (clone-1) was a selective inhibitor of RGD-dependent ligand binding to ␣v␤6 in isolated receptor assays (IC 50 ‫؍‬ 20 nM), and in cell adhesion assays (IC 50 ‫؍‬ 50 M). DLXXL peptides were highly specific inhibitors of ␣v␤6-fibronectin interaction as synthetic scrambled or reversed DLXXL peptides were inactive. NH 2 -and COOH-terminal modifications of the flanking amino acids suggested that the preceding two and a single trailing amino acid were also involved in interaction with ␣v␤6. The DLXXL sequence is present in several matrix components and in the ␤ chain of many integrins. Although there is as yet no precise biological role known for DLXXL, it is clearly a specific inhibitory sequence for integrin ␣v␤6 which has been unrecognized previously.Integrins are a family of heterodimeric class I transmembrane receptors involved in numerous cell-matrix and cell-cell adhesion phenomena (1). They can be grouped roughly into three classes: the ␤1 series, which are ubiquitous receptors for extracellular matrix (2); the ␤2 series, which are activatable on leukocytes and are triggered during the inflammatory response (3); and the ␣v series, which bind and mediate the cell response to provisional extracellular matrices found during wound repair and other pathological processes (4).The integrins ␣5␤1 (5), ␣IIb␤3 (6), ␣8␤1 (7), ␣v␤1 (8), ␣v␤3(9), and ␣v␤6 (10) all bind the Arg-Gly-Asp-(RGD) peptide sequence in fibronectin, where it is presented in a constrained loop (11). Soluble RGD-containing peptides can inhibit the interaction of each of these integrins with fibronectin. However, to analyze the function of individual fibronectin receptors in a particular cellular environment it is useful to have more specific inhibitors, and a variety of inhibitory antibodies, modified peptides, and non-peptidic substances has been developed. However, as yet no inhibitor has been discovered specific for ␣v␤6. ␣v␤6 is a rare integrin, induced during repair processes in epithelia (10, 12). Its only known specificities are for fibronectin (10), where it can be the dominant receptor me...

Mental health nurses should be trained in brief CBT for schizophrenia to supplement case management, family interventions and expert therapy for treatment resistance.

This study investigated similarities and differences in the experience of auditory hallucinations, paranoia, and childhood trauma in schizophrenia and borderline personality disorder (BPD). Patients with clinical diagnoses of schizophrenia or BPD were interviewed using the Structured Clinical Interviews for DSM-IV. Axes 1 and 2 and auditory hallucinations, paranoia, and childhood trauma were assessed. A total of 111 patients participated; 59 met criteria for schizophrenia, 33 for BPD, and 19 for both. The groups were similar in their experiences of voices, including the perceived location of them, but they differed in frequency of paranoid delusions. Those with a diagnosis of BPD, including those with schizophrenia comorbidity, reported more childhood trauma, especially emotional abuse. BPD and schizophrenia frequently coexist, and this comorbidity has implications for diagnostic classification and treatment. Levels of reported childhood trauma are especially high in those with a BPD diagnosis, whether they have schizophrenia or not, and this requires assessment and appropriate management.

The molecular mechanisms of alphavbeta3 integrin affinity regulation have important biological implications in tumour development, wound repair and angiogenesis. We expressed, purified and characterized recombinant forms of human alphavbeta3 (r-alphavbeta3) and compared the activation state of these with alphavbeta3 in its cellular environment. The ligand specificity and selectivity of recombinant full-length and double transmembrane truncations of r-alphavbeta3 cloned in BacPAK6 vectors and expressed in Sf9 and High Five insect cells were compared with those of native placental alphavbeta3 and the receptor in situ on the cell surface. r-alphavbeta3 integrins were purified by affinity chromatography from detergent extracts of cells (full-length), and from the culture medium of cells expressing double-truncated r-alphavbeta3. r-alphavbeta3 had the same epitopes, ligand-binding specificities, bivalent cation requirements and susceptibility to RGD-containing peptides as native alphavbeta3. On M21-L4 melanoma cells, alphavbeta3 mediated binding to vitronectin, but not to fibrinogen unless activated with Mn2+. Non-activated alphaIIbbeta3 integrin as control in M21-L-IIb cells had the opposite profile, mediating binding to fibrinogen, but not to vitronectin unless activated with Mn2+. Thus these receptors had moderate to low ligand affinity. In marked contrast, purified alphavbeta3 receptors, with or without transmembrane and cytoplasmic domains, were constitutively of high affinity and able to bind strongly to vitronectin, fibronectin and fibrinogen under physiological conditions. Our data suggest that, in contrast with the positive regulation of alphaIIbbeta3 in situ, intracellular controls lower the affinity of alphavbeta3, and the cytoplasmic domains may act as a target for negative regulators of alphavbeta3 activity.