Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre-existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction.

Anti-Slavic imagery in German radical nationalist discourse at the turn of the twentieth century: a prelude to Nazi ideology?

By applying methods of cognitive metaphor theory, Jaworska examines metaphorical scenarios employed in the discourse of anti-Slavism, which featured prominently in radical nationalist propaganda in Germany at the turn of the twentieth century. She does so by analysing metaphorical expressions used to refer to the Polish population living in the eastern provinces of Prussia, in the so-called Ostmark. Her article is based on an analysis of a range of pamphlets and newspaper articles written by some of the leading figures of two nationalist organizations: the Pan-German League (Alldeutscher Verband) and the Eastern Marches Society(Ostmarkenverein). The main research questions it addresses are: What kind of metaphoric scenarios were used to depict the Polish minority, and to what extent were the metaphorical patterns of anti-Slavic imagery similar to those employed in the antisemitic propaganda of the Nazi era? Is there a discursive continuity between the radical nationalism of imperial Germany and the National Socialism of the Third Reich at the level of metaphorical scenarios? Ultimately, Jaworska attempts to contribute to a better understanding of the cognitive mechanisms underlying radical and essentially racist attitudes.

Dominant components of the Thoroughbred metabolome characterised by 1H‐NMR spectroscopy: a metabolite atlas of common biofluids

Summary Reasons for performing study: Metabonomics is emerging as a powerful tool for disease screening and investigating mammalian metabolism. This study aims to create a metabolic framework by producing a preliminary reference guide for the normal equine metabolic milieu. Objectives: To metabolically profile plasma, urine and faecal water from healthy racehorses using high resolution 1H-NMR spectroscopy and to provide a list of dominant metabolites present in each biofluid for the benefit of future research in this area. Study design: This study was performed using seven Thoroughbreds in race training at a single time-point. Urine and faecal samples were collected non-invasively and plasma was obtained from samples taken for routine clinical chemistry purposes. Methods: Biofluids were analysed using 1H-NMR spectroscopy. Metabolite assignment was achieved via a range of 1D and 2D experiments. Results: A total of 102 metabolites were assigned across the three biological matrices. A core metabonome of 14 metabolites was ubiquitous across all biofluids. All biological matrices provided a unique window on different aspects of systematic metabolism. Urine was the most populated metabolite matrix with 65 identified metabolites, 39 of which were unique to this biological compartment. A number of these were related to gut microbial host co-metabolism. Faecal samples were the most metabolically variable between animals; acetate was responsible for the majority (28%) of this variation. Short chain fatty acids were the predominant features identified within this biofluid by 1H-NMR spectroscopy. Conclusions: Metabonomics provides a platform for investigating complex and dynamic interactions between the host and its consortium of gut microbes and has the potential to uncover markers for health and disease in a variety of biofluids. Inherent variation in faecal extracts along with the relative abundance of microbial-mammalian metabolites in urine and invasive nature of plasma sampling, infers that urine is the most appropriate biofluid for the purposes of metabonomic analysis.

National interest to global reform: patterns of reasoning in British foreign policy discourse

Discussion of the national interest often focuses on how Britain's influence can be maximized, rather than on the goals that influence serves. Yet what gives content to claims about the national interest is the means-ends reasoning which links interests to deeper goals. In ideal-typical terms, this can take two forms. The first, and more common, approach is conservative: it infers national interests and the goals they advance from existing policies and commitments. The second is reformist: it starts by specifying national goals and then asks how they are best advanced under particular conditions. New Labour's foreign policy discourse is notable for its explicit use of a reformist approach. Indeed, Gordon Brown's vision of a 'new global society' not only identifies global reform as a key means of fulfilling national goals, but also thereby extends the concept of the national interest well beyond a narrow concern with national security.

Challenging climate change and migration discourse: different understandings of time-scale and temporality in the Maldives

This article draws on ongoing research in the Maldives to explore differences between elite and non-elite perceptions of climate change and migration. It argues that, in addition to variations in perceptions based on diverse knowledge, priorities and agendas, there exists a more fundamental divergence based upon different understandings of the time-scale of climate change and related ideas of urgency and crisis. Specifically, elites tend to focus on a distant future which is generally abstracted from people’s everyday lived realities, as well as utilise the language of a climate change-induced migration ‘crisis’ in their discussions about impacts in a manner not envisaged by non-elites. The article concludes that, rather than unproblematically mapping global, external facing narratives wholesale onto ordinary people’s lives and experiences, there needs to be more dialogue between elites and non-elites on climate change and migration issues. These perspectives should be integrated more effectively in the development of policy interventions designed to help people adapt to the impacts of global environmental change.

Half-remembered quotations from mostly forgotten speeches: the limits of Labour’s European policy discourse

This article uses discourse analysis to study the continuities in British foreign policy thinking within the Labour party from the 1960s to the present day. Using representative extracts from speeches by Hugh Gaitskell, Harold Wilson, Tony Blair and Gordon Brown, it identifies the ideational consis- tencies in the leaders’ attitudes to: Empire; federalism in the EEC/EU; and laying down conditions that have to be met before any constructive engagement with ‘Europe’ can be countenanced. We argue that these consistencies, spanning a 50-year period, exemplify a certain stagnation both within Labour’s European discourses and within British foreign policy thinking more widely. We develop the idea that Labour party thinking has been crucially framed by both small ‘c’ conser- vative and upper-case Conservative ideology, popularised by Winston Churchill in his ‘three circles’ model of British foreign policy.

Dominant role of greenhouse-gas forcing in the recovery of Sahel rainfall

Sahelian summer rainfall, controlled by the West African monsoon, exhibited large-amplitude multidecadal variability during the twentieth century. Particularly important was the severe drought of the 1970s and 1980s, which had widespread impacts1–6. Research into the causes of this drought has identified anthropogenic aerosol forcing3,4,7 and changes in sea surface temperatures (SSTs; refs 1,2,6,8–11) as the most important drivers. Since the 1980s, there has been some recovery of Sahel rainfall amounts2–6,11–14, although not to the pre-drought levels of the 1940s and 1950s. Here we report on experiments with the atmospheric component of a state-of-the-art global climate model to identify the causes of this recovery. Our results suggest that the direct influence of higher levels of greenhouse gases in the atmosphere was the main cause, with an additional role for changes in anthropogenic aerosol precursor emissions. We find that recent changes in SSTs, although substantial, did not have a significant impact on the recovery. The simulated response to anthropogenic greenhouse-gas and aerosol forcing is consistent with a multivariate fingerprint of the observed recovery, raising confidence in our findings. Although robust predictions are not yet possible, our results suggest that the recent recovery in Sahel rainfall amounts is most likely to be sustained or amplified in the near term.

Teaching and learning Chinese: heritage language classroom discourse in Montreal

This paper explores issues of teaching and learning Chinese as a heritage language in a Chinese heritage language school, the Zhonguo Saturday School, in Montreal, Quebec. With a student population of more than 1000, this school is the largest of the eight Chinese Heritage Language schools in Montreal. Students participating in this study were from seven different classes (grade K, two, three, four, five, six, and special class), their ages ranging from 4 to 13 years. The study took place over a period of two years between 2000 and 2002. Focusing on primary level classroom discourse and drawing on the works of Vygotsky and Bakhtin, I examine how teachers and students use language to communicate, and how their communication mediates teaching, learning and heritage language acquisition. Data sources include classroom observations, interviews with students and their teachers, students’ writings, and video and audio taping of classroom activities. Implications for heritage language development and maintenance are discussed with reference to the findings of this study.

The neoliberal way of war: a critical analysis of contemporary British security in policy and practice.

Dominant paradigms of causal explanation for why and how Western liberal-democracies go to war in the post-Cold War era remain versions of the 'liberal peace' or 'democratic peace' thesis. Yet such explanations have been shown to rest upon deeply problematic epistemological and methodological assumptions. Of equal importance, however, is the failure of these dominant paradigms to account for the 'neoliberal revolution' that has gripped Western liberal-democracies since the 1970s. The transition from liberalism to neoliberalism remains neglected in analyses of the contemporary Western security constellation. Arguing that neoliberalism can be understood simultaneously through the Marxian concept of ideology and the Foucauldian concept of governmentality – that is, as a complementary set of 'ways of seeing' and 'ways of being' – the thesis goes on to analyse British security in policy and practice, considering it as an instantiation of a wider neoliberal way of war. In so doing, the thesis draws upon, but also challenges and develops, established critical discourse analytic methods, incorporating within its purview not only the textual data that is usually considered by discourse analysts, but also material practices of security. This analysis finds that contemporary British security policy is predicated on a neoliberal social ontology, morphology and morality – an ideology or 'way of seeing' – focused on the notion of a globalised 'network-market', and is aimed at rendering circulations through this network-market amenable to neoliberal techniques of government. It is further argued that security practices shaped by this ideology imperfectly and unevenly achieve the realisation of neoliberal 'ways of being' – especially modes of governing self and other or the 'conduct of conduct' – and the re-articulation of subjectivities in line with neoliberal principles of individualism, risk, responsibility and flexibility. The policy and practice of contemporary British 'security' is thus recontextualised as a component of a broader 'neoliberal way of war'.

Robustness despite uncertainty: regional climate data reveal the dominant role of humans in explaining global extinctions of Late Quaternary megafauna

Debate over the late Quaternary megafaunal extinctions has focussed on whether human colonisation or climatic changes were more important drivers of extinction, with few extinctions being unambiguously attributable to either. Most analyses have been geographically or taxonomically restricted and the few quantitative global analyses have been limited by coarse temporal resolution or overly simplified climate reconstructions or proxies. We present a global analysis of the causes of these extinctions which uses high-resolution climate reconstructions and explicitly investigates the sensitivity of our results to uncertainty in the palaeological record. Our results show that human colonisation was the dominant driver of megafaunal extinction across the world but that climatic factors were also important. We identify the geographic regions where future research is likely to have the most impact, with our models reliably predicting extinctions across most of the world, with the notable exception of mainland Asia where we fail to explain the apparently low rate of extinction found in in the fossil record. Our results are highly robust to uncertainties in the palaeological record, and our main conclusions are unlikely to change qualitatively following minor improvements or changes in the dates of extinctions and human colonisation.

Moisture can be the dominant environmental parameter governing cadaver decomposition in soil

Forensic taphonomy involves the use of decomposition to estimate postmortem interval (PMI) or locate clandestine graves. Yet, cadaver decomposition remains poorly understood, particularly following burial in soil. Presently, we do not know how most edaphic and environmental parameters, including soil moisture, influence the breakdown of cadavers following burial and alter the processes that are used to estimate PMI and locate clandestine graves. To address this, we buried juvenile rat (Rattus rattus) cadavers (∼18 g wet weight) in three contrasting soils from tropical savanna ecosystems located in Pallarenda (sand), Wambiana (medium clay), or Yabulu (loamy sand), Queensland, Australia. These soils were sieved (2 mm), weighed (500 g dry weight), calibrated to a matric potential of -0.01 megapascals (MPa), -0.05 MPa, or -0.3 MPa (wettest to driest) and incubated at 22 °C. Measurements of cadaver decomposition included cadaver mass loss, carbon dioxide-carbon (CO2-C) evolution, microbial biomass carbon (MBC), protease activity, phosphodiesterase activity, ninhydrin-reactive nitrogen (NRN) and soil pH. Cadaver burial resulted in a significant increase in CO2-C evolution, MBC, enzyme activities, NRN and soil pH. Cadaver decomposition in loamy sand and sandy soil was greater at lower matric potentials (wetter soil). However, optimal matric potential for cadaver decomposition in medium clay was exceeded, which resulted in a slower rate of cadaver decomposition in the wettest soil. Slower cadaver decomposition was also observed at high matric potential (-0.3 MPa). Furthermore, wet sandy soil was associated with greater cadaver decomposition than wet fine-textured soil. We conclude that gravesoil moisture content can modify the relationship between temperature and cadaver decomposition and that soil microorganisms can play a significant role in cadaver breakdown. We also conclude that soil NRN is a more reliable indicator of gravesoil than soil pH.

Discourse-sensitive clitic-doubled dislocations in heritage Spanish

This experimental study tests the predictions of the Interface Hypothesis (Sorace, 2011, 2012) using two constructions whose appropriateness depends on monitoring discourse information: Clitic Left Dislocation and Fronted Focus. Clitic Left Dislocation relates a dislocated and clitic-doubled object to an antecedent activated in previous discourse, while Fronted Focus does not relate the fronted constituent to a discourse antecedent. The Interface Hypothesis argues that speakers in language contact situations experience difficulties when they have to integrate syntactic with discourse information. We tested four groups of native speakers on these constructions: Spanish monolinguals, bilinguals with more than 7 years residence in the US, intermediate and advanced proficiency heritage speakers. Our findings suggest that attrition has not set in the adult L2 bilingual speakers, and that the heritage speakers perform similarly to the monolingual and the adult sequential bilingual natives.

Pragmatic solutions for syntactic problems: Understanding some L2 syntactic errors in terms of discourse-pragmatic deficits

Contemporary research in generative second language (L2) acquisition has attempted to address observable target-deviant aspects of L2 grammars within a UG-continuity framework (e.g. Lardiere 2000; Schwartz 2003; Sprouse 2004; Prévost & White 1999, 2000). With the aforementioned in mind, the independence of pragmatic and syntactic development, independently observed elsewhere (e.g. Grodzinsky & Reinhart 1993; Lust et al. 1986; Pacheco & Flynn 2005; Serratrice, Sorace & Paoli 2004), becomes particularly interesting. In what follows, I examine the resetting of the Null-Subject Parameter (NSP) for English learners of L2 Spanish. I argue that insensitivity to associated discoursepragmatic constraints on the discursive distribution of overt/null subjects accounts for what appear to be particular errors as a result of syntactic deficits. It is demonstrated that despite target-deviant performance, the majority must have native-like syntactic competence given their knowledge of the Overt Pronoun Constraint (Montalbetti 1984), a principle associated with the Spanish-type setting of the NSP.