Protein phosphatase 2A mediates resensitization of the neurokinin 1 receptor

Activated G protein-coupled receptors (GPCRs) are phosphorylated and interact with beta-arrestins, which mediate desensitization and endocytosis. Endothelin-converting enzyme-1 (ECE-1) degrades neuropeptides in endosomes and can promote recycling. Although endocytosis, dephosphorylation, and recycling are accepted mechanisms of receptor resensitization, a large proportion of desensitized receptors can remain at the cell surface. We investigated whether reactivation of noninternalized, desensitized (phosphorylated) receptors mediates resensitization of the substance P (SP) neurokinin 1 receptor (NK(1)R). Herein, we report a novel mechanism of resensitization by which protein phosphatase 2A (PP2A) is recruited to dephosphorylate noninternalized NK(1)R. A desensitizing concentration of SP reduced cell-surface SP binding sites by only 25%, and SP-induced Ca(2+) signals were fully resensitized before cell-surface binding sites started to recover, suggesting resensitization of cell-surface-retained NK(1)R. SP induced association of beta-arrestin1 and PP2A with noninternalized NK(1)R. beta-Arrestin1 small interfering RNA knockdown prevented SP-induced association of cell-surface NK(1)R with PP2A, indicating that beta-arrestin1 mediates this interaction. ECE-1 inhibition, by trapping beta-arrestin1 in endosomes, also impeded SP-induced association of cell-surface NK(1)R with PP2A. Resensitization of NK(1)R signaling required both PP2A and ECE-1 activity. Thus, after stimulation with SP, PP2A interacts with noninternalized NK(1)R and mediates resensitization. PP2A interaction with NK(1)R requires beta-arrestin1. ECE-1 promotes this process by releasing beta-arrestin1 from NK(1)R in endosomes. These findings represent a novel mechanism of PP2A- and ECE-1-dependent resensitization of GPCRs.

Endogenous business cycles with frictional labour markets

We present a neoclassical model of capital accumulation with frictional labour markets. Under standard parameter values the equilibrium of the model is indeterminate and consequently displays expectations-driven business cycles – so-called endogenous business cycles. We study the properties of such cycles, and find that the model predicts the high autocorrelation in output growth and the hump-shaped impulse response of output found in US data – important features that existing endogenous real business cycle models fail to explain. The indeterminacy of the equilibrium stems from job search externalities and does not rely on increasing returns to scale as in most models.

The credit relationship between Henry III and merchants of Douai and Ypres, 1247-70

This article looks at an important but neglected aspect of medieval sovereign debt, namely ‘accounts payable’ owed by the Crown to merchants and employees. It focuses on the unusually well-documented relationship between Henry III, King of England between 1216 and 1272, and Flemish merchants from the towns of Douai and Ypres, who provided cloth on credit to the royal wardrobe. From the surviving royal documents, we reconstruct the credit advanced to the royal wardrobe by the merchants of Ypres and Douai for each year between 1247 and 1270, together with the king's repayment history. The interactions between the king and the merchants are then analysed. The insights from this analysis are applied to the historical data to explain the trading decisions made by the merchants during this period, as well as why the strategies of the Yprois sometimes differed from those of the Douaissiens.

Which words are hard for autistic children to learn?

Motivated by accounts of concept use in autistic spectrum disorder (ASD), and a computational model of weak central coherence (O’Loughlin & Thagard, 2000) we examined comprehension and production vocabulary in typically-developing children, and those with ASD and Down syndrome (DS). Controlling for frequency, familiarity, length, and imageability, Colorado Meaningfulness played a hitherto unremarked role in the vocabularies of children with ASD. High Colorado Meaningful words were underrepresented in the comprehension vocabularies of 2- to 12-year-olds with ASD. The Colorado Meaningfulness of a word is a measure of how many words can be associated with it. Situations in which high Colorado Meaningfulness words are encountered are typically highly variable, and words with High Colorado Meaningfulness often involve extensive use of context. Our data suggest that the number of contexts in which a particular word can appear has a role in determining vocabulary in ASD. This suggestion is consistent with the weak central coherence theory of autism.

Indexical predicates

We discuss the challenge to truth-conditional semantics presented by apparent shifts in extension of predicates such as ‘red’. We propose an explicit indexical semantics for ‘red’ and argue that our account is preferable to the alternatives on conceptual and empirical grounds.

The causal inefficacy of content

The paper begins with the assumption that psychological event tokens are identical to or constituted from physical events. It then articulates a familiar apparent problem concerning the causal role of psychological properties. If they do not reduce to physical properties, then either they must be epiphenomenal or any effects they cause must also be caused by physical properties, and hence be overdetermined. It then argues that both epiphenomenalism and over-determinationism are prima facie perfectly reasonable and relatively unproblematic views. The paper proceeds to argue against Kim’s (Kim, 2000, 2005) attempt to articulate a plausible version of reductionism. It is then argued that psychological properties, along with paradigmatically causally efficacious macro-properties, such as toughness, are causally inefficacious in respect of their possessor’s typical effects, because they are insufficiently distinct from those effects. It is finally suggested that the distinction between epiphenomenalism and overdeterminationism may be more terminological than real.

Music and Metaphor

Peter Kivy’s contour theory provides a promising explanation of the way we describe instrumental music as expressive of emotions. I argue that if, unlike Kivy, we emphasise the metaphorical character of such descriptions, the contour theory, as a strategy for unpacking such metaphors, can be defended convincingly against common objections. This approach is more satisfactory than those of Scruton and Peacocke, who make much of metaphorical experiences, but leave the underlying metaphors unexplained. Moreover, it gives the contour theory a wider scope than Kivy intended, for even very specific narrative descriptions of music in non-musical terms are perfectly legitimate as long as they are presented, and justified, as metaphors, that is, as mere comparisons, rather than as interpretative claims about the music’s actual contents.

Military competition and the emergence of nationalism: putting the logic of political survival into historical context

This essay aims to make a contribution to the conversation between IR and nationalism literatures by considering a particular question: What is the relationship between interstate military competition and the emergence of nationalism as a potent force in world politics? The conventional wisdom among international security scholars, especially neorealists, holds that nationalism can be more or less treated like a “technology” that allowed states to extract significant resources as well as manpower from their respective populations. This paper underlines some of the problems involved with this perspective and pushes forward an interpretation that is based on the logic of political survival. I argue that nationalism’s emergence as a powerful force in world politics followed from the “mutation” and absorption of the universalistic/cosmopolitan republican ideas that gained temporary primacy in Europe during the eighteenth century into particularistic nationalist ideologies. This transformation, in turn, can be best explained by the French Revolution’s dramatic impacts on rulers’ political survival calculi vis-à-vis both interstate and domestic political challenges. The analysis offered in this essay contributes to our understanding of the relationship between IR and nationalism while also highlighting the potential value of the political survival framework for exploring macrohistorical puzzles.

The arbitrariness and normativity of social conventions

This paper investigates a puzzling feature of social conventions: the fact that they are both arbitrary and normative. We examine how this tension is addressed in sociological accounts of conventional phenomena. Traditional approaches tend to generate either synchronic accounts that fail to consider the arbitrariness of conventions, or diachronic accounts that miss central aspects of their normativity. As a remedy, we propose a processual conception that considers conventions as both the outcome and material cause of much human activity. This conceptualization, which borrows from the économie des conventions as well as critical realism, provides a novel perspective on how conventions are nested and defined, and on how they are established, maintained and challenged.

Speech therapy after stroke: trial shows only that practice varies

Bowen and colleagues’ methods and conclusions raise concerns.1 At best, the trial evaluates the variability in current practice. In no way is it a robust test of treatment. Two communication impairments (aphasia and dysarthria) were included. In the post-acute stage spontaneous recovery is highly unpredictable, and changes in the profile of impairment during this time are common.2 Both impairments manifest in different forms,3 which may be more or less responsive to treatment. A third kind of impairment, apraxia of speech, was not excluded but was not targeted in therapy. All three impairments can and do co-occur. Whether randomised controlled trial designs can effectively cope with such complex disorders has been discussed elsewhere.4 Treatment was defined within terms of current practice but was unconstrained. Therefore, the treatment group would have received a variety of therapeutic approaches and protocols, some of which may indeed be ineffective. Only 53% of the contact time with a speech and language therapist was direct (one to one), the rest was impairment based therapy. In contrast, all of the visitors’ time was direct contact, usually in conversation. In both groups, the frequency and length of contact time varied. We already know that the transfer from impairment based therapy to functional communication can be limited and varies across individuals.5 However, it is not possible to conclude from this trial that one to one impairment based therapy should be replaced. For that, a well defined impairment therapy protocol must be directly compared with a similarly well defined functional communication therapy, with an attention control.

Community development in sustainable livelihoods approaches: an introduction

This article introduces sustainable livelihoods approaches, explaining what they are and how they have emerged. It examines how different organizations have taken up a sustainable livelihoods approach, and considers whether in so doing they have drawn on community development thinking and practice. It is found that community development is largely absent from sustainable livelihoods thinking and contended that part of the reason lies with the locally situated character of community development practice, which makes it difficult for externally driven sustainable livelihoods interventions to systematically incorporate community-level methods and practices. More fundamentally, sustainable livelihoods approaches embody a technocratic development drive, which is at odds with the principles, ethos and values that underpin much development work.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Children of the revolution: fathers and sons in antifascist DEFA films

The article looks at three antifascist films from the 1980s by the East German film company DEFA: Jürgen Brauer's Pugowitza (1981), Egon Schlegel's Die Schüsse der Arche Noah (1983), and Helmut Dziuba's Jan auf der Zille (1986), which during this final decade of the East German state re-examine an ideologically seminal constellation of the GDR's official antifascism – the relationship between antifascist father and son. Linking generational and political succession, the father-son relationship helped to legitimise the GDR as a state in which the young continued the antifascist fight of the old communists against the Nazi dictatorship. From the 1950s on, DEFA films contributed to the visualisation of this relationship, codifying it not only as heroic but also as ‘natural’: the assumed innocence of the communist son was meant to naturalise the father's antifascist/communist cause. The 1980s saw this naturalised political succession questioned. By re-telling the canonised father-son story, the three films visualise the generational antifascist contract as flawed. Re-deploying the son's assumed innocence in a critique of the father, they explore new endings to the antifascist story and revive the discussion of categories like ‘victim’ and ‘perpetrator’.// Der Aufsatz untersucht drei antifaschistische Filme der ostdeutschen Filmgesellschaft DEFA aus den 1980er Jahren: Jürgen Brauers Pugowitza (1981), Egon Schlegels Die Schüsse der Arche Noah (1983) und Helmut Dziubas Jan auf der Zille (1986). Alle drei Filme wurden im letzten Jahrzehnt der DDR gedreht und greifen eine ideologisch tragende Konstellation des offiziellen DDR-Antifaschismus auf – die Beziehung zwischen antifaschistischem Vater und Sohn. In der Vater-Sohn-Beziehung verband sich Generationenabfolge mit politischer Nachkommenschaft, eine Verbindung, die half, die DDR als einen Staat zu legitimieren, in dem die Jungen den antifaschistischen Kampf der alten Kommunisten gegen die Nazi-Diktatur weiterführten. Seit den 1950er Jahren beteiligte sich die DEFA an der Visuali-sierung dieser Beziehung und kodifizierte sie nicht nur als heldenhaft, sondern auch als ‘natürlich’: die behauptete Unschuld der kommunistschen Söhne diente dazu, den antifaschistisch-kommunistischen Kampf der Väter zu naturalisieren. Die solcher Art politisch interpretierte Generationenabfolge verlor ihre Natürlichkeit, als sie in den 1980er Jahren kritisch befragt wurde. Im nochmaligen Erzählen der kanonisierten Vater-Sohn-Geschichte wird die Brüchigkeit des antifaschistischen Gesellschaftsvertrags in allen drei Filmen sichtbar. Die vermeintliche Unschuld der Söhne wird nun zu einer Kritik der Väter genutzt, wobei die Filme ein neues Ende für die antifaschistische Geschichte erkunden und die Debatte über Kategorien wie ‘Opfer’ und ‘Täter’ wieder aufnehmen.

Random Prism: a noise-tolerant alternative to Random Forests

Ensemble learning can be used to increase the overall classification accuracy of a classifier by generating multiple base classifiers and combining their classification results. A frequently used family of base classifiers for ensemble learning are decision trees. However, alternative approaches can potentially be used, such as the Prism family of algorithms that also induces classification rules. Compared with decision trees, Prism algorithms generate modular classification rules that cannot necessarily be represented in the form of a decision tree. Prism algorithms produce a similar classification accuracy compared with decision trees. However, in some cases, for example, if there is noise in the training and test data, Prism algorithms can outperform decision trees by achieving a higher classification accuracy. However, Prism still tends to overfit on noisy data; hence, ensemble learners have been adopted in this work to reduce the overfitting. This paper describes the development of an ensemble learner using a member of the Prism family as the base classifier to reduce the overfitting of Prism algorithms on noisy datasets. The developed ensemble classifier is compared with a stand-alone Prism classifier in terms of classification accuracy and resistance to noise.

Weaning diet induces sustained metabolic phenotype shift in the pig and influences host response to Bifidobacterium lactis NCC2818

Background: The process of weaning causes a major shift in intestinal microbiota and is a critical period for developing appropriate immune responses in young mammals. Objective: To use a new systems approach to provide an overview of host metabolism and the developing immune system in response to nutritional intervention around the weaning period. Design: Piglets (n¼14) were weaned onto either an eggbased or soya-based diet at 3 weeks until 7 weeks, when all piglets were switched onto a fish-based diet. Half the animals on each weaning diet received Bifidobacterium lactis NCC2818 supplementation from weaning onwards. Immunoglobulin production from immunologically relevant intestinal sites was quantified and the urinary 1H NMR metabolic profile was obtained from each animal at post mortem (11 weeks). Results: Different weaning diets induced divergent and sustained shifts in the metabolic phenotype, which resulted in the alteration of urinary gut microbial co-metabolites, even after 4 weeks of dietary standardisation. B lactis NCC2818 supplementation affected the systemic metabolism of the different weaning diet groups over and above the effects of diet. Additionally, production of gut mucosa-associated IgA and IgM was found to depend upon the weaning diet and on B lactis NCC2818 supplementation. Conclusion: The correlation of urinary 1H NMR metabolic profile with mucosal immunoglobulin production was demonstrated, thus confirming the value of this multiplatform approach in uncovering non-invasive biomarkers of immunity. This has clear potential for translation into human healthcare with the development of urine testing as a means of assessing mucosal immune status. This might lead to early diagnosis of intestinal dysbiosis and with subsequent intervention, arrest disease development. This system enhances our overall understanding of pathologies under supra-organismal control.