164 research outputs found
KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.
Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.This work was supported by the Wellcome Trust
(098497/Z/12/Z; 077016/Z/05/Z; 096106/Z/11/Z) (ISF and LRP), Medical
Research Council (MC_U106179471) (NW), NIHR Cambridge Biomedical
Research Centre (ISF, IB and SOR), and European Research Council (ISF).
This study makes use of data generated by the UK10K Consortium
(WT091310). A full list of the investigators who contributed to the generation
of the data is available from http://www.UK10K.org.This is the final published version. It first appeared at http://www.cell.com/abstract/S0092-8674%2813%2901276-2
Household networks and emergent territory: a GIS study of Chumash households, villages and rock-art in South-Central California
Elite households of the Californian Chumash have been studied in order to understand the development of Late Holocene hunter-gatherer alliance networks. Equally, models of what has been termed âtribelet territoriesâ have been used to describe land ownership within larger Californian concepts. Surprisingly little research has explicitly addressed issues of how such territories may have developed. In this article, we turn to DeLandaâs philosophy of social complexity to consider how Chumash households may have underpinned the development of tribelet territories and the political implications for their articulation with wider alliances. Importantly, utilizing Geographic Information Systems (GIS), we analyse potential mobility patterns in relation to households, villages and rock-art locales in a case from the Emigdiano Chumash. The results suggest that the painting of rock art was imbricated within processes of territorialization, and that the local placement of art reflects which villages were home to particularly high-status households
Impaired contractile function of the supraspinatus in the acute period following a rotator cuff tear
Background: Rotator cuff (RTC) tears are a common clinical problem resulting in adverse changes to the muscle, but there is limited information comparing histopathology to contractile function. This study assessed supraspinatus force and susceptibility to injury in the rat model of RTC tear, and compared these functional changes to histopathology of the muscle.
Methods: Unilateral RTC tears were induced in male rats via tenotomy of the supraspinatus and infraspinatus. Maximal tetanic force and susceptibility to injury of the supraspinatus muscle were measured in vivo at day 2 and day 15 after tenotomy. Supraspinatus muscles were weighed and harvested for histologic analysis of the neuromuscular junction (NMJ), intramuscular lipid, and collagen.
Results: Tenotomy resulted in eventual atrophy and weakness. Despite no loss in muscle mass at day 2 there was a 30% reduction in contractile force, and a decrease in NMJ continuity and size. Reduced force persisted at day 15, a time point when muscle atrophy was evident but NMJ morphology was restored. At day 15, torn muscles had decreased collagen-packing density and were also more susceptible to contraction-induced injury.
Conclusion: Muscle size and histopathology are not direct indicators of overall RTC contractile health. Changes in NMJ morphology and collagen organization were associated with changes in contractile function and thus may play a role in response to injury. Although our findings are limited to the acute phase after a RTC tear, the most salient finding is that RTC tenotomy results in increased susceptibility to injury of the supraspinatus
Border Insecurity: Reading Transnational Environments in Jim Lynchâs Border Songs
This article applies an eco-critical approach to contemporary American fiction about the Canada-US border, examining Jim Lynchâs portrayal of the British Columbia-Washington borderlands in his 2009 novel Border Songs. It argues that studying transnational environmental actors in border textsâin this case, marijuana, human migrants, and migratory birdsâhelps illuminate the contingency of political boundaries, problems of scale, and discourses of risk and security in cross-border regions after 9/11. Further, it suggests that widening the analysis of trans-border activity to include environmental phenomena productively troubles concepts of nature and regional belonging in an era of climate change and economic globalization. Cet article propose une lecture Ă©cocritique de la fiction Ă©tatsunienne contemporaine portant sur la frontiĂšre entre le Canada et les Ătats-Unis, en Ă©tudiant le portrait donnĂ© par Jim Lynch de la rĂ©gion frontaliĂšre entre la Colombie-Britannique et Washington dans son roman Border Songs, paru en 2009. Lâarticle soutient que lâĂ©tude, dans les textes sur la frontiĂšre, des acteurs environnementaux transnationaux â dans ce cas-ci, la marijuana, les migrants humains et les oiseaux migratoires â jette un jour nouveau sur la contingence des limites territoriales politiques, des problĂšmes dâĂ©chelle et des discours sur le risque et la sĂ©curitĂ© des rĂ©gions transfrontaliĂšres aprĂšs les Ă©vĂšnements du 11 septembre 2001. Il suggĂšre Ă©galement quâen Ă©largissant lâanalyse de lâactivitĂ© transfrontaliĂšre pour y inclure les phĂ©nomĂšnes environnementaux, on brouille de façon productive les concepts de nature et dâappartenance rĂ©gionale dâune Ă©poque marquĂ©e par les changements climatiques et la mondialisation de lâĂ©conomie
Neptune to the Common-wealth of England (1652): the republican Britannia and the continuity of interests
In the seventeenth century, John Kerrigan reminds us, âmodels of empire did not always turn on monarchyâ. In this essay, I trace a vision of âNeptuneâs empireâ shared by royalists and republicans, binding English national interest to British overseas expansion. I take as my text a poem entitled âNeptune to the Common-wealth of Englandâ, prefixed to Marchamont Nedhamâs 1652 English translation of Mare Clausum (1635), John Seldenâs response to Mare Liberum (1609) by Hugo Grotius. This minor work is read alongside some equally obscure and more familiar texts in order to point up the ways in which it speaks to persistent cultural and political interests. I trace the afterlife of this verse, its critical reception and its unique status as a fragment that exemplifies the crossover between colonial republic and imperial monarchy at a crucial moment in British history, a moment that, with Brexit, remains resonant
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