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There would be little adaptive value in a complex communication system like human language if there were no ways to detect and correct problems. A systematic comparison of conversation in a broad sample of the world’s languages reveals a universal system for the real-time resolution of frequent breakdowns in communication. In a sample of 12 languages of 8 language families of varied typological profiles we find a system of ‘other-initiated repair’, where the recipient of an unclear message can signal trouble and the sender can repair the original message. We find that this system is frequently used (on average about once per 1.4 minutes in any language), and that it has detailed common properties, contrary to assumptions of radical cultural variation. Unrelated languages share the same three functionally distinct types of repair initiator for signalling problems and use them in the same kinds of contexts. People prefer to choose the type that is the most specific possible, a principle that minimizes cost both for the sender being asked to fix the problem and for the dyad as a social unit. Disruption to the conversation is kept to a minimum, with the two-utterance repair sequence being on average no longer that the single utterance which is being fixed. The findings, controlled for historical relationships, situation types and other dependencies, reveal the fundamentally cooperative nature of human communication and offer support for the pragmatic universals hypothesis: while languages may vary in the organization of grammar and meaning, key systems of language use may be largely similar across cultural groups. They also provide a fresh perspective on controversies about the core properties of language, by revealing a common infrastructure for social interaction which may be the universal bedrock upon which linguistic diversity rests.

The principle of personalisation is widespread across the UK’s public sector, but precisely what thismeans is unclear. A number of theoretical typologies have been proposed but there has been little empirical study of how personalisation is translated into practice on the frontline. We address this gap through analysis of a unique dataset: over 200 audio and video recordings of work-focused interviews in Jobcentre Plus offices. Through detailed analysis of these recordings, we show that personalisation reflects two key dimensions: the substantive (what advisers do) and the procedural (how they do it). We illustrate these dimensions, showing how each represents a continuum, and propose a typology of personalisation in practice, reflecting how the dimensions interact. We conclude with some thoughts on the relevance of our findings for advisory practice in the future under the Coalition government’s new Work Programme.

A state-of-the art review of conversational repair, with contributions from internationally recognized leaders in the field of conversation analysis.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists have been shown to have a therapeutic benefit in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). In this study, we investigated the mechanism by which the PPARalpha agonist gemfibrozil induces immune deviation and protects mice from EAE. We demonstrated that treatment with gemfibrozil increases expression of the Th2 transcription factor GATA-3 and decreases expression of the Th1 transcription factor T-bet in vitro and directly ex vivo. These changes correlated with an increase in nuclear PPARalpha expression. Moreover, the protective effects of PPARalpha agonists in EAE were shown to be partially dependent on IL-4 and to occur in a receptor-dependent manner. PPARalpha was demonstrated, for the first time, to regulate the IL-4 and IL-5 genes and to bind the IL-4 promoter in the presence of steroid receptor coactivator-1, indicating that PPARalpha can directly transactivate the IL-4 gene. Finally, therapeutic administration of PPARalpha agonists ameliorated clinically established EAE, suggesting that PPARalpha agonists may provide a treatment option for immune-mediated inflammatory diseases.

In the development and progression of cancer, tumor suppressor genes may be silenced by mechanisms such as methylation. Thus the discovery of new genes silenced by methylation may uncover new tumor suppressor genes, and improve our understanding of cancer biology. In this study we investigated the methylation of 19 genes in esophageal squamous cell carcinoma. Methylation was measured in 10 of these genes in esophageal squamous cell carcinoma cell lines: CDH13, CLDN6, C16orf62, FBN2, FNBP1, ID4, RBP1, RBP4, TFPI2 and TMEFF2. To determine if there was a correlation between DNA methylation and gene silencing, each cell line was cultured with or without the demethylating drug 5-aza-2'-deoxycytidine (aza-dC). For 6 genes (CLDN6, FBN2, RBP1, RBP4, TFPI2 and TMEFF2) there was an association between reduction of methylation and increase in mRNA expression in the demethylated cell lines. The frequency of the methylation of these 6 genes in esophageal squamous cell carcinoma resection specimens was also investigated. All 6 genes showed more frequent methylation in the tumor than the matched proximal resection margin of uninvolved esophagus. There was a significant difference in the frequency of methylation and in the extent of the methylation between the cancer and the margin tissues for CLDN6, FBN2, TFPI2 and TMEFF2 (P=0.0007, P=0.0048 P=0.0002 and P

Brain abscesses result from a pyogenic parenchymal infection commonly initiated by Gram-positive bacteria such as Staphylococcus aureus. Although the host immune response elicited following infection is essential for effective bacterial containment, this response also contributes to the significant loss of brain parenchyma by necrosis that may be reduced by modulating the inflammatory response. Ciglitazone, a PPAR-gamma agonist with anti-inflammatory properties, was evaluated for its ability to influence the course of brain abscess development when treatment was initiated 3 days following infection. Interestingly, abscess-associated bacterial burdens were significantly lower following ciglitazone administration, which could be explained, in part, by the finding that ciglitazone enhanced S. aureus phagocytosis by microglia. In addition, ciglitazone attenuated the expression of select inflammatory mediators during brain abscess development including inducible NO synthase, TNF-alpha, IL-1beta, CXCL2, and CCL3. Unexpectedly, ciglitazone also accelerated brain abscess encapsulation, which was typified by the heightened expression of fibronectin and alpha-smooth muscle actin-positive myofibroblasts. Collectively, through its ability to attenuate excessive inflammation and accelerate abscess encapsulation, ciglitazone may effectively sequester brain abscesses and limit bacterial dissemination.

The role of peroxisome proliferator-activated receptors (PPARs) in altering lipid and glucose metabolism is well established. More recent studies indicate that PPARs also play critical roles in controlling immune responses. We and others have previously demonstrated that PPAR-γ agonists modulate the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This review will discuss the cellular and molecular mechanisms by which these agonists are believed to modulate disease. The therapeutic potential of PPAR-γ agonists in the treatment of multiple sclerosis will also be considered.

PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in the regulation of lipid metabolism, energy balance, artherosclerosis and glucose control. Recent studies suggest that they play an important role in regulating inflammation. This review will focus on PPAR-α regulation of the immune response. We describe how PPAR-α regulates differentiation of T cells by transactivation and/or interaction with other transcription factors. Moreover, PPAR-α agonists have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in mice, suggesting that they could provide a therapy for human autoimmune diseases such as multiple sclerosis.

Accumulation of amyloid-β peptide (Aβ) appears to contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutic hope for the prevention or removal of Aβ deposits has been placed in strategies involving immunization against the Aβ peptide. Initial Aβ immunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to Aβ. Specifically, CD4+ Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Aβ immunization in the treatment of AD. Interleukin (IL)-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, Aβ1−42 synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-γ agonist 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ2 suppressed the Aβ-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-γ agonists may be effective in modulating the development of AD.