Replicating viral vector platform exploits alarmin signals for potent CD8⁺ T cell-mediated tumour immunotherapy.

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTL <sup>eff</sup> ) responses. Conversely, the induction of protective tumour-specific CTL <sup>eff</sup> and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTL <sup>eff</sup> responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTL <sup>eff</sup> influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy

Sport, War and Democracy in Classical Athens

This article concerns the paradox of athletics in classical Athens. Democracy may have opened up politics to every class of Athenian but it had little impact on sporting participation. The city’s athletes continued to drawn predominantly from the upper class. It comes as a surprise then that lower-class Athenians actually esteemed athletes above every other group in the public eye, honoured them very generously when they won, and directed a great deal of public and private money to sporting competitions and facilities. In addition athletics escaped the otherwise persistent criticism of upper-class activities in the popular culture of the democracy. The research of social scientists on sport and aggression suggests this paradox may have been due to the cultural overlap between athletics and war under the Athenian democracy. The article concludes that the practical and ideological democratization of war by classical Athens legitimized and supported upper-class sport

Unagreement is an illusion

This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11049-015-9311-yThis paper proposes an analysis of unagreement, a phenomenon involving an apparent mismatch between a definite third person plural subject and first or second person plural subject agreement observed in various null subject languages (e.g. Spanish, Modern Greek and Bulgarian), but notoriously absent in others (e.g. Italian, European Portuguese). A cross-linguistic correlation between unagreement and the structure of adnominal pronoun constructions suggests that the availability of unagreement depends on whether person and definiteness are hosted by separate heads (in languages like Greek) or bundled on a single head (i.e. pronominal determiners in languages like Italian). Null spell-out of the head hosting person features high in the extended nominal projection of the subject leads to unagreement. The lack of unagreement in languages with pronominal determiners results from the interaction of their syntactic structure with the properties of the vocabulary items realising the head encoding both person and definiteness. The analysis provides a principled explanation for the cross-linguistic distribution of unagreement and suggests a unified framework for deriving unagreement, adnominal pronoun constructions, personal pronouns and pro

Long-term results of syndactyly correction by the trilobed flap technique focusing on hand function and quality of life.

Syndactyly is usually corrected surgically during the first years of life. The trilobed flap, a surgical method that does not require skin grafting, was developed in the 1990s and the short-term results were comparable with previously reported techniques. Here we report on long-term outcomes, focusing on how children perceive their hand function and quality of life when they grow up. A total of 19 patients (29 web spaces) were operated on between 1990 and 2000, and followed-up 16 years later with questionnaires and clinical tests. The patients reported low QuickDASH scores, normal sensibility and dexterity, and minor cold intolerance. Only two reoperations, due to early web creep, were needed. The condition minimally affected the choice of occupations, leisure activities and perceptions of appearance. The trilobed flap technique for release of syndactyly provides a good long-term outcome with good hand function and minimal impact on the quality of life

Hand Function in Cerebral Palsy. Report of 367 Children in a Population-Based Longitudinal Health Care Program

Purpose To describe aspects of hand function in a total population of children with cerebral palsy (CP). Methods Upper extremity data were collected for 367 children who were born between 1992 and 2001 and were registered in a population-based health care program for children with CP. Hand function was classified according to the Manual Ability Classification System (MACS), the House functional classification, and the Zancolli classification. The type of spastic thumb-in-palm deformity was evaluated according to House. Results In the total population of children with CP aged 4 to 14 years, 60% had more than minor problems with hand function (>MACS I). Independence in age-relevant, daily manual activities (MACS I-II) was noted in 87% of children with spastic unilateral CP and in 63% of children with spastic bilateral CP, but in only 20% of children with dyskinetic CP. According to the House functional classification, both hands were spontaneously and independently used in 55% of children (House 7-8), whereas 5% did not use either of their hands (House 0). Minor increase of flexor muscle tone (Zancolli level 1) was found in 69% of all children. Only 2% were in level 3 in both hands. Spastic thumb-in-palm deformity in 1 hand was found in 25% and in both hands in another 15%. Conclusions Limitations in hand function are common in all types of CP, but characteristics of the disability vary considerably between different CP subtypes. The MACS classification is useful to evaluate how well children can handle objects in daily activities. The House functional classification describes grip function in each hand separately; the Zancolli classification of finger and wrist extension and the classification of thumb-in-palm deformity according to House give an estimate of dynamic spasticity. All these classifications were shown to be useful in a population-based health care program, but further studies of the psychometric properties are required. (J Hand Surg 2008;33A:1337-1347. Copyright (C) 2008 by the American Society for Surgery of the Hand. All rights reserved.

Antibody bivalency improves antiviral efficacy by inhibiting virion release independently of Fc gamma receptors

Across the animal kingdom, multivalency discriminates antibodies from all other immunoglobulin superfamily members. The evolutionary forces conserving multivalency above other structural hallmarks of antibodies remain, however, incompletely defined.Here, we engineer monovalent either Fc-competent or -deficient antibody formats to investigate mechanisms of protection of neutralizing antibodies (nAbs) and non-neutralizing antibodies (nnAbs) in virus-infected mice. Antibody bivalency enables the tethering of virions to the infected cell surface, inhibits the release of virions in cell culture, and suppresses viral loads in vivo independently of Fc gamma receptor (Fc gamma R) interactions. In return, monovalent antibody formats either do not inhibit virion release and fail to protect in vivo or their protective efficacy is largely Fc gamma R dependent. Protection in mice correlates with virus-release-inhibiting activity of nAb and nnAb rather than with their neutralizing capacity.These observations provide mechanistic insights into the evolutionary conservation of antibody bivalency and help refining correlates of nnAb protection for vaccine development