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Yiddish stands out as a severely endangered language which, apparently, refuses to die. This chapter will focus on new speakers of Yiddish, a non-territorial language which nonetheless has distinct cultural and ethnic associations. Data for this chapter have been collected over the course of the last few years with new Yiddish speakers in London, Brussels and Edinburgh. What is apparent are the distinct discourses of, and attitudes toward traditional and new speakers of Yiddish. When some commentators, such as Katz (2015) Beer (2009), Wex (2009) or Fishman (2001a) talk about the Yiddish of new (and here we can translate this as mostly ‘secular’) speakers, it is constructed as imperfect or faulty, being, as Fishman considers, ‘replete with Anglicisms and Germanisms’, since these speakers ‘curiously reject that which lives and is growing while they cleave to that which is admittedly wilting before their very eyes and is patently beyond their ability to revernacularize’ (Fishman 2001a: 89). As far as traditional (i.e. mainly religious) speakers are concerned however, similar features can be overlooked: ‘[i]n contrast to many other bi-and multilingual contexts, parents never corrected or complained about simultaneities in girls’ efforts to speak Yiddish’ (Fader 2009: 93). Yiddish is thus an example par excellence of a divided speech community, a term often used in minority language communities (see references to this in Chapter 2).

The case studies on Breton, Yiddish and Lemko have shown how three quite distinct groups of speakers/language users engage in discourses of legitimacy and authenticity in the face of language attrition in the wider community. The reduction in the use of minority languages is something which is widely viewed as problematic and, as previously mentioned in Chapter 1, is often accompanied by ‘an ideologically charged discursive space’ with an over-arching ‘ideology of language endangerment’ (Dobrin, Austin and Nathan 2007: 59). In connection with this, M.C. Jones (1998a: 323) wonders if the appearance of non-traditional forms of minority languages is ‘the pre-terminal phase of some dying languages in particular socio-political contexts’; and for Makoni and Pennycook (2007: 26), changes, such as the appearance of new speakers, may indicate a ‘shift as a reflection of a creative adaptation to new contexts’. In this chapter, and with the above in mind, I examine the ways in which the issues of authenticity and legitimacy are being tackled by users of two other languages which have either been deemed extinct (and now revived) or ‘barely alive’ (Fishman 2001b: 227). The idea that problems over authenticity and legitimacy are possibly resolved with the disappearance of ‘native’ speakers is one that is occasionally voiced, as Pentecouteau found: While engaged in fieldwork, I have heard some activists who are very committed to the Breton movement say that they are waiting for the total disappearance of native Breton speakers so that they can work without this ‘burden’ … the behaviour of new speakers does little or nothing to validate an already existing knowledge of the language. (My translation) Lors de travaux d’observation, j’ai entendu des militants tres investis dans l’emsav dire attendre la disparition totale des bretonnants de naissance afin de pouvoir travailler sans ce « fardeau » … l’action des nouveaux locuteurs ne porte pas ou peu a valoriser une connaissance encore vivante. (Pentecouteau 2002: 175)

The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.

A homogenous TR-FRET-based in vitro coupling assay for the MAP3Ks-MEK1-ERK2 kinase cascade was established and was used to screen for inhibitors of the ERK/MAPK pathway. A series of coumarin derivatives were identified from the screen. These compounds potently inhibit the activation of the unactivated human MEK1 by upstream MAP3Ks (including BRAF and COT), but do not inhibit the activity of the activated MEK1. In addition, the potency of these compounds in inhibiting MEK1 activation is not affected by varying the ATP concentration, suggesting that these inhibitors are not competitive with ATP. As expected, the coumarin compounds potently inhibit LPS-induced TNFalpha production and ERK phosphorylation in THP-1 cells, with the most potent compound having an IC(50) of 90nM. Molecular modeling studies suggest that these coumarins bind to an allosteric site in the inactive conformation of MEK1. This site has been shown to be utilized by the biarylamine series of MEK inhibitors such as PD318088. Very interestingly, the identified coumarin derivatives are almost identical to a series of inhibitors recently reported that block LPS-induced TNFalpha production. Our findings have therefore raised the possibility that other naturally occurring or synthetic coumarins with anti-cancer and anti-inflammatory activities might exert their biological function through the inhibition of MEK1.

Attempts to revitalize Breton have led to the appearance of a learner variety of the language which is by no means universally accepted. This article reviews the major trends that commentators have taken with regard to this variety –néo-breton– and, as the variety of Breton most likely to survive into the twenty-first century, the likely domains where this variety will be used are examined. Differences with traditional Breton are discussed, as is the controversial nature of néo-breton in the eyes of somecommentators and native speakers. Within the field of language death studies, the appearance of ‘neo-’ languages has implications for the stages a language experiencing attrition goes through and whether these ‘neo’ varieties do realistically represent a future for the endangered language. An examination of the differing expectations of various groups invo l ved in the debate seeks to establish common ground between them, through making explicit the different aims of the groups and where these aims converge. As tentativas por revitalizar o bretón conduciron á aparición dunha variedade de principiantes que non é unanimemente aceptada. Este artigo pasa en revista as principais tendencias que os inve s t i gadores adoptaron fronte a esta variedade –o neobretón– e mais examina (como a variedade do bretón con máis posibilidades de supervivencia no século XXI) os campos onde será máis probable que se use. Coméntanse as diferenzas co bretón tradicional, tal e como se reflicte na controvertida natureza que posúe o neobretón para algúns investigadores e locutores nativos. Dentro do eido de estudo da morte das linguas, a aparición das ‘neo-’linguas posúe implicacións nos estadios que atravesa unha lingua en proceso de perda, e tamén en se estas ‘neo’ variedades realmente representan unha posibilidade de futuro para as linguas en perigo. O noso exame das diferentes ex p e c t a t ivas de varios dos grupos involucrados no debate pretende establecer un marco común entre os mesmos, explicitando os seus diferentes obxectivos e a súa posible evolución.

Antibody phage display libraries combined with high-throughput selections have recently demonstrated tremendous promise to create the next generation of renewable, recombinant antibodies to study proteins and their many post-translational modification states; however, many challenges still remain, such as optimized antibody scaffolds. Recently, a single-chain fragment antigen binding (Fab) (scFab) format, in which the carboxy-terminus of the light chain is linked to the amino-terminus of the heavy chain, was described to potentially combine the high display levels of a single-chain fragment variable with the high stability of purified Fabs. However, this format required removal of the interchain disulfide bond to achieve modest display levels and subsequent bacterial expression resulted in high levels of aggregated scFab, hindering further use of scFabs. Here, we developed an improved scFab format that retains the interchain disulfide bond by increasing the linker length between the light and heavy chains to improve display and bacterial expression levels to 1-3 mg/L. Furthermore, rerouting of the scFab to the co-translational signal recognition particle pathway combined with reengineering of the signal peptide sequence results in display levels 24-fold above the original scFab format and 3-fold above parent Fab levels. This optimized scFab scaffold can be easily reformatted in a single step for expression in a bacterial or mammalian host to produce stable (Tm of 81 °C), predominantly monomeric (>90%) antibodies at a high yield. Ultimately, this new scFab format will advance high-throughput antibody generation platforms to discover the next generation of research and therapeutic antibodies.

“Revitalized” or “neo” Breton as a contested variety exhibits a number of features of a language which has been revitalized from the “bottom-up”, including a lack of acceptance of certain neologisms, particularly those coined (it is claimed) from a “purist” or “nationalist” provenance. Here, we explore how these neologisms are contested through the prism of language ideology and how competing claims to Breton ‘authenticity’ are being played out in a variety of arenas, including internet fora.

The European Union is home to national, regional and minority languages, only some of which have some recognition and the support of state language policies. To demonstrate this we proceed in three steps. First, we demonstrate that the current approach of European institutions and nation-states, providing support for languages is at odds with the commitment for equality of citizens, i.e. language communities and their members on the entire territory of the Union. Second, we demonstrate that most European languages with a stringently defined homeland territory are likely to survive, while those with no support from territorially defined language policies struggle to compete for speakers with the majority/official state languages. Thirdly, we discuss regional efforts to increase the currency of what is frequently seen as regional variety of the state language Samogitian, Latgalian and Voru in three new EU member-states undergoing processes of nation-cum-institution building. Finally, we review minority language activism of languages, ‘officially distinct’ from the state language, Kashubian and Silesian, contending that activism of these communities reflects the stark centripetal logic in state language policies. The salience of non-standard idioms, as we conclude, reflects both the European emphasis on linguistic diversity and nation-state linguistic cohesion – both trends resulting in ‘language sectarianism.’

If the linguistic landscape encompasses a variety of signs and (place)names in various territories, regions and urban centres (Landry and Bourhis, 1997), then our attention tends to be drawn, not unreasonably, to the visual aspect of such ‘linguistic objects that mark the public space’ (Ben-Rafael, 2009, p. 40; our emphasis). It is this simultaneous focus on both the linguistic and the visual that leads us to locate linguistic landscapes in a wider, semiotic framework, since the linguistic aspect is but one component in an interface between cultural, social, economic and (re)productive processes; moreover, ‘landscapes possess “semiotic” properties, in other words, they contain signs in them that can be decoded by those with intimate knowledge of them’ (Selman, 2006, p. 53). Our approach follows recent research in the area which seeks to examine wider fields of investigation than just the linguistic, such as ‘visual images, non-verbal communication, architecture and the built environment’ (Jaworski and Thurlow, 2010, p. 2). As a result, semiotic analysis takes place on a variety of levels and in the case of signage in minority languages, the indexicality of the sign tends to dominate debates, though decoding can also focus on the iconic aspects. Such indexicality, we argue, is very often decoded through the prism of language ideology, especially in situations of linguistic minoritization.

SummaryIn response to enteric pathogens, the inflamed intestine produces antimicrobial proteins, a process mediated by the cytokines IL-17 and IL-22. Salmonella enterica serotype Typhimurium thrives in the inflamed intestinal environment, suggesting that the pathogen is resistant to antimicrobials it encounters in the intestinal lumen. However, the identity of these antimicrobials and corresponding bacterial resistance mechanisms remain unknown. Here, we report that enteric infection of rhesus macaques and mice with S. Typhimurium resulted in marked Il-17- and IL-22-dependent intestinal epithelial induction and luminal accumulation of lipocalin-2, an antimicrobial protein that prevents bacterial iron acquisition. Resistance to lipocalin-2, mediated by the iroBCDE iroN locus, conferred a competitive advantage to the bacterium in colonizing the inflamed intestine of wild-type but not of lipocalin-2-deficient mice. Thus, resistance to lipocalin-2 defines a specific adaptation of S. Typhimurium for growth in the inflamed intestine.

Background & Aims: We used the rhesus macaque model to study the effects of the cag pathogenicity island ( cag PAI) on the H pylori host-pathogen interaction. Methods: H pylori– specific pathogen-free (SPF) monkeys were experimentally challenged with wild-type (WT) H pylori strain J166 (J166WT, n=4) or its cag PAI isogenic knockout (J166Δ cag PAI, n=4). Animals underwent endoscopy before and 1, 4, 8, and 13 weeks after challenge. Gastric biopsies were collected for quantitative culture, histopathology, and host gene expression analysis. Results: Quantitative cultures showed that all experimentally challenged animals were infected with J166WT or its isogenic J166Δ cag PAI. Histopathology demonstrated that inflammation and expansion of the lamina propria were attenuated in animals infected with J166Δ cag PAI compared with J166WT. Microarray analysis showed that of the 119 up-regulated genes in the J166WT-infected animals, several encode innate antimicrobial effector proteins, including elafin, siderocalin, DMBT1, DUOX2, and several novel paralogues of human-β defensin-2. Quantitative RT-PCR confirmed that high-level induction of each of these genes depended on the presence of the cag PAI. Immunohistochemistry confirmed increased human-β defensin-2 epithelial cell staining in animals challenged with J166WT compared with either J166Δ cag PAI-challenged or uninfected control animals. Conclusions: We propose that one function of the cag PAI is to induce an antimicrobial host response that may serve to increase the competitive advantage of H pylori in the gastric niche and could even provide a protective benefit to the host.

Pseudouridine (Psi) synthases catalyze the formation of one or more specific Psis in structured RNAs. Five families of Psi synthases have been characterized based on sequence homology. Pus10 has no significant sequence homology to these defined families and therefore represents a new family of Psi synthases. Initial characterization studies show that an archael Pus10 catalyzes the universally conserved Psi55 in tRNA. We present here the crystal structure of human Pus10 at 2.0 A resolution, which is the first structural description from this novel Psi synthase family. Pus10 is a crescent-shaped molecule with two domains, the universally conserved Psi synthase catalytic domain and a THUMP-containing domain, which is unique to the Pus10 family. Superposition of the catalytic domains of Pus10 and other Psi synthases identifies the full set of conserved Psi synthase active site residues indicating that Pus10 likely employs a similar catalytic mechanism to other Psi synthases. The Pus10 active site is located in a deep pocket of a basic cleft adjacent to flexible thumb and forefinger loops, which could provide further stabilization for binding the RNA substrate. Modeling studies demonstrate that the cleft between the catalytic and accessory domain is large enough and electrostatically compatible to accommodate an RNA stem and support the role of the N-terminal domain as an accessory RNA-binding domain.

The substrate activity screening method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain low nanomolar 1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolically labile aldehyde pharmacophore with the nitrile pharmacophore provided inhibitors with moderate potency for cathepsin S. The inhibitors showed good selectivity over cathepsins B and L but no selectivity over cathepsin K. X-ray structures of two crystal forms (1.5 and 1.9 A) of a complex between cathepsin S and a triazole inhibitor incorporating a chloromethyl ketone pharmacophore guided the design of triazole substrates with increased cleavage efficiency and selectivity for cathepsin S over cathepsins B, L, and K. Conversion of select substrates to nitrile inhibitors yielded a low molecular weight (414 Da) and potent (15 nM) cathepsin S inhibitor that showed1000-fold selectivity over cathepsins B, L, and K.

This paper reports some of the findings of a questionnaire survey of the social, moral and religious attitudes of 578 fifth formers in three Roman Catholic comprehensive schools and one local authority secondary school in the autumn of 1973. School and home variables related to differences in the scores obtained on six scales were identified and a brief review of student responses to open‐ended questions on religion carried out. The findings indicate that while the Catholic schools do differ significantly in some respects from the local authority school, there is also a large measure of overlap in the beliefs and values of the students. The data also showed that high levels of anti‐intellectualism and acceptance of the traditional role of the woman in the home are not features common to all Catholic schools. The need for more broadly based research is stressed.