Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

It was shown previously that abnormal prohormone processing or inactive proconverting enzymes that are responsible for this processing cause profound obesity. Our laboratory demonstrated earlier that in the diet-induced obesity (DIO) state, the appetite-suppressing neuropeptide -melanocyte-stimulating hormone ( -MSH) is reduced, yet the mRNA of its precursor protein proopiomelanocortin (POMC) remained unaltered. It was also shown that the DIO condition promotes the development of endoplasmic reticulum (ER) stress and leptin resistance. In the current study, using an in vivo model combined with in vitro experiments, we demonstrate that obesity-induced ER stress obstructs the post-translational processing of POMC by decreasing proconverting enzyme 2, which catalyzes the conversion of adrenocorticotropin to -MSH, thereby decreasing -MSH peptide production. This novel mechanism of ER stress affecting POMC processing in DIO highlights the importance of ER stress in regulating central energy balance in obesity.Fil: Cakir, Isin. Brown University; Estados UnidosFil: Cyr, Nicole E.. Brown University; Estados UnidosFil: Perello, Mario. Brown University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Litvinov, Bogdan Patedakis. Brown University; Estados UnidosFil: Romero, Amparo. Brown University; Estados UnidosFil: Stuart, Ronald C.. Brown University; Estados UnidosFil: Nillni, Eduardo A.. Brown University; Estados Unido

A Three Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotype E Subtypes.

Human botulism is most commonly caused by botulinum neurotoxin (BoNT) serotypes A, B, and E. For this work, we sought to develop a human monoclonal antibody (mAb)-based antitoxin capable of binding and neutralizing multiple subtypes of BoNT/E. Libraries of yeast-displayed single chain Fv (scFv) antibodies were created from the heavy and light chain variable region genes of humans immunized with pentavalent-toxoid- and BoNT/E-binding scFv isolated by Fluorescence-Activated Cell Sorting (FACS). A total of 10 scFv were isolated that bound one or more BoNT/E subtypes with nanomolar-level equilibrium dissociation constants (KD). By diversifying the V-regions of the lead mAbs and selecting for cross-reactivity, we generated three scFv that bound all four BoNT/E subtypes tested at three non-overlapping epitopes. The scFvs were converted to IgG that had KD values for the different BoNT/E subtypes ranging from 9.7 nM to 2.28 pM. An equimolar combination of the three mAbs was able to potently neutralize BoNT/E1, BoNT/E3, and BoNT/E4 in a mouse neutralization assay. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing multiple BoNT/E subtypes. A derivative of the three-antibody combination (NTM-1633) is in pre-clinical development with an investigational new drug (IND) application filing expected in 2018

Tracking the reflexivity of the (dis)engaged citizen: some methodological reflections

The relationship between governments and citizens in many contemporary democracies is haunted by uncertainty and sociologists face the task of listening effectively to citizens’ own reflections on this uncertain relationship. This article reflects on the qualitative methodology of a recently completed UK project which used a combination of diary and multiple interviews/ focus groups to track over a fieldwork period of up to a year citizens’ reflections on their relationship to a public world and the contribution to this of their media consumption. In particular, the article considers how the project’s multiple methods enabled multiple angles on the inevitable artificiality and performative dimension of the diary process, resulting in rich data on people’s complex reflections on the uncertain position of the contemporary citizen

Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

It was shown previously that abnormal prohormone processing or inactive proconverting enzymes that are responsible for this processing cause profound obesity. Our laboratory demonstrated earlier that in the diet-induced obesity (DIO) state, the appetite-suppressing neuropeptide -melanocyte-stimulating hormone ( -MSH) is reduced, yet the mRNA of its precursor protein proopiomelanocortin (POMC) remained unaltered. It was also shown that the DIO condition promotes the development of endoplasmic reticulum (ER) stress and leptin resistance. In the current study, using an in vivo model combined with in vitro experiments, we demonstrate that obesity-induced ER stress obstructs the post-translational processing of POMC by decreasing proconverting enzyme 2, which catalyzes the conversion of adrenocorticotropin to -MSH, thereby decreasing -MSH peptide production. This novel mechanism of ER stress affecting POMC processing in DIO highlights the importance of ER stress in regulating central energy balance in obesity.Fil: Cakir, Isin. Brown University; Estados UnidosFil: Cyr, Nicole E.. Brown University; Estados UnidosFil: Perello, Mario. Brown University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Litvinov, Bogdan Patedakis. Brown University; Estados UnidosFil: Romero, Amparo. Brown University; Estados UnidosFil: Stuart, Ronald C.. Brown University; Estados UnidosFil: Nillni, Eduardo A.. Brown University; Estados Unido

Impossible protest: noborders in Calais

Since the closure of the Red Cross refugee reception centre in Sangatte, undocumented migrants in Calais hoping to cross the border to Britain have been forced to take refuge in a number of squatted migrant camps, locally known by all as ‘the jungles.’ Unauthorised shanty-like residences built by the migrants themselves, living conditions in the camps are very poor. In June 2009, European ‘noborder’ activists set up a week-long protest camp in the area with the intention of confronting the authorities over their treatment of undocumented migrants. In this article, we analyse the June 2009 noborder camp as an instance of ‘immigrant protest.’ Drawing on ethnographic materials and Jacques Rancière's work on politics and aesthetics, we construct a typology of forms of border control through which to analyse the different ways in which the politics of the noborder camp were staged, performed and policed. Developing a critique of policing practices which threatened to make immigrant protest ‘impossible’, we highlight moments of protest which, through the affirmation of an ‘axiomatic’ equality, disrupted and disarticulated the borders between citizens and non-citizens, the political and non-political

Integration against the state: irregular migrants’ agency between deportation and regularisation in the United Kingdom

Reducing the number of foreigners residing unlawfully within the borders of a state requires either their removal or the legalisation of their presence within the territory. Increasingly, governments also employ measures of internal control and limit irregular migrants’ access to rights and services in order to encourage them to leave autonomously. This article aims to contribute to current debates on how to conceptualise and account for the agency that irregular migrants themselves exercise in such contexts. Within critical migration and citizenship studies, many of their everyday actions have been described as ‘acts of citizenship’ but also as instances of ‘becoming imperceptible’, neither of which captures the whole range of strategies irregular migrants employ to strengthen their fragile position vis-à-vis the state. I argue that conceptualising their agency in terms of (self-)integration allows us to account for both: practices through which they actively become political subjects as well as those that precisely constitute a deliberate refusal to do so. Empirically, this is underpinned by an analysis of recent policy developments in the United Kingdom and a series of semi-structured interviews I conducted during 8 months of fieldwork in London with migrants experiencing different kinds and degrees of irregularity

Refining of metal melts by filtration method

The article describes the prerequisites of filtration refining of metal melts. When filtering the liquid metals the refining effect is caused by the deposition on the filter surface of suspended non-metallic particles in the melt, and by the release of the non-metallic phase directly from the melt. Along with this the mechanism of melt refining from a superequilibrium dissolved impurity is realized when filtering as a result of the reaction course of chemical binding of the impurity element

Emotions and Digital Well-being. The rationalistic bias of social media design in online deliberations

In this chapter we argue that emotions are mediated in an incomplete way in online social media because of the heavy reliance on textual messages which fosters a rationalistic bias and an inclination towards less nuanced emotional expressions. This incompleteness can happen either by obscuring emotions, showing less than the original intensity, misinterpreting emotions, or eliciting emotions without feedback and context. Online interactions and deliberations tend to contribute rather than overcome stalemates and informational bubbles, partially due to prevalence of anti-social emotions. It is tempting to see emotions as being the cause of the problem of online verbal aggression and bullying. However, we argue that social media are actually designed in a predominantly rationalistic way, because of the reliance on text-based communication, thereby filtering out social emotions and leaving space for easily expressed antisocial emotions. Based on research on emotions that sees these as key ingredients to moral interaction and deliberation, as well as on research on text-based versus non-verbal communication, we propose a richer understanding of emotions, requiring different designs of online deliberation platforms. We propose that such designs should move from text-centred designs and should find ways to incorporate the complete expression of the full range of human emotions so that these can play a constructive role in online deliberations

Citizenship and Inclusion: Rethinking the Analytical Category of Noncitizenship

The paper problematises the category of noncitizenship. It traces its trajectory in accounts of inclusive citizenship and argues that it is difficult to theorise it as a distinct theoretical category outside of citizenship. To support this argument, the paper distinguishes between a pluralist, political and democratic variant of accounts of inclusive citizenship and it shows how they all end up reducing noncitizenship to a journey to citizenship. To overcome this limit, the paper develops the idea of subversive politicisation and suggests that injustices and inequalities can be challenged without falling back on the vocabulary of citizenship

Citizenship, Justice and the Right to the Smart City

This paper provides an introduction to the smart city and engages with its idea and ideals from a critical social science perspective. After setting out in brief the emergence of smart cities and current key debates, we note a number of practical, political and normative questions relating to citizenship, justice, and the public good that warrant examination. The remainder of the paper provides an initial framing for engaging with these questions. The first section details the dominant neoliberal conception and enactment of smart cities and how this works to promote the interests of capital and state power and reshape governmentality. We then detail some of the ethical issues associated with smart city technologies and initiatives. Having set out some of the more troubling aspects of how social relations are produced within smart cities, we then examine how citizens and citizenship have been conceived and operationalised in the smart city to date. We then follow this with a discussion of social justice and the smart city. In the final section, we explore the notion of the ‘right to the smart city’ and how this might be used to recast the smart city in emancipatory and empowering ways