‘The longest suicide vote in history’: the Labour Party leadership election of 2015

The Labour leadership contest of 2015 resulted in the election of the veteran Left-wing backbencher, Jeremy Corbyn, who clearly defeated the early favourite, Andy Burnham. Yet Corbyn enjoyed very little support among Labour MPs, and his victory plunged the PLP into turmoil, particularly as he was widely viewed as incapable of leading the Party to victory in the 2020 general election. Given that, much of the established academic literature on Party leadership contests emphasises the ability to foster unity, and thereby render a party electable, as two of the key criteria for electing a new leader, coupled with overall competence, important questions are raised about how and why the Labour Party chose someone to lead them who clearly does not meet these criteria. We will argue that whilst these are the natural priorities of MPs when electing a new leader, in Corbyn’s case, much of the extra-parliamentary Labour Party was more concerned about ideological conviction and purity of principles, regardless of how far these diverged from public opinion. This was especially true of those who signed-up to the Labour Party following the 2015 general election defeat. Indeed, many of these only did so after Corbyn had become a candidate. This clearly suggests a serious tension between maximising intra-party democracy and ensuring the electability of the parliamentary party itself

A constitutive law for dense granular flows

A continuum description of granular flows would be of considerable help in predicting natural geophysical hazards or in designing industrial processes. However, the constitutive equations for dry granular flows, which govern how the material moves under shear, are still a matter of debate. One difficulty is that grains can behave like a solid (in a sand pile), a liquid (when poured from a silo) or a gas (when strongly agitated). For the two extreme regimes, constitutive equations have been proposed based on kinetic theory for collisional rapid flows, and soil mechanics for slow plastic flows. However, the intermediate dense regime, where the granular material flows like a liquid, still lacks a unified view and has motivated many studies over the past decade. The main characteristics of granular liquids are: a yield criterion (a critical shear stress below which flow is not possible) and a complex dependence on shear rate when flowing. In this sense, granular matter shares similarities with classical visco-plastic fluids such as Bingham fluids. Here we propose a new constitutive relation for dense granular flows, inspired by this analogy and recent numerical and experimental work. We then test our three-dimensional (3D) model through experiments on granular flows on a pile between rough sidewalls, in which a complex 3D flow pattern develops. We show that, without any fitting parameter, the model gives quantitative predictions for the flow shape and velocity profiles. Our results support the idea that a simple visco-plastic approach can quantitatively capture granular flow properties, and could serve as a basic tool for modelling more complex flows in geophysical or industrial applications.Comment: http://www.nature.com/nature/journal/v441/n7094/abs/nature04801.htm

Radical nostalgia, progressive patriotism and Labour's 'English problem'

‘Progressive patriots’ have long argued that Englishness can form the basis of a transformative political project, whether based on an historic tradition of resistance to state power or an open and cosmopolitan identity. However, this article suggests that the politics of Englishness present a number of specific dilemmas for Labour. First the historical narrative of a radical tradition in British history is not straightforwardly English and cannot easily be used to support a competitive politics of nationhood, in the way that disaffected English identifiers might desire. Second, the deliberately alternative nature of this ‘radical nostalgic’ narrative makes it an unlikely basis for a unifying national story. It is also at odds with Labour’s status as a successful party of government, committed to using the power of the British state, rather than opposing it. Finally, while ‘everyday Englishness’ may well align with core Labour values and be less socially conservative, intolerant or racially exclusive than it is often described, its very nature as an everyday practice, rather than a political identity makes it difficult for Labour to co-opt

Tales of the unexpected: the selection of British party leaders since 1963

Jeremy Corbyn’s election as Leader of the Labour Party in 2015 stunned observers and practitioners of British politics alike. In this article, we first outline a theoretical framework that purports to explain why political parties operating in parliamentary systems choose the leaders they do. We then examine 32 leadership successions involving five major British parties since 1963, and note that many of these were unexpected, in that they were triggered by unforeseen circumstances, such as the sudden death or resignation of the incumbent. Examining each party in turn, we briefly explain why the winners won and identify at least eight cases (a quarter of our sample) where a candidate widely expected to prevail at the outset was ultimately defeated by a ‘dark horse’, ‘second favourite’ or even ‘rank outsider’. Of these, Corbyn’s election in 2015 was the most unexpected and, consistent with the findings of studies of party leadership conventions in other parliamentary systems, namely Canada and Spain, suggests that ideological and policy concerns are sometimes more important than considerations of party unity and electability, especially when a leadership contest is dominated by party activists

High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai, India.

Adverse events (AEs) among HIV-infected patients with multidrug-resistant tuberculosis (MDR-TB) receiving anti-TB and antiretroviral treatments (ART) are under-researched and underreported. Hypothyroidism is a common AE associated with ethionamide, p-aminosalicylic acid (PAS), and stavudine. The aim of this study was to determine the frequency of and risk factors associated with hypothyroidism in HIV/MDR-TB co-infected patients

Kinome-wide interaction modelling using alignment-based and alignment-independent approaches for kinase description and linear and non-linear data analysis techniques

<p>Abstract</p> <p>Background</p> <p>Protein kinases play crucial roles in cell growth, differentiation, and apoptosis. Abnormal function of protein kinases can lead to many serious diseases, such as cancer. Kinase inhibitors have potential for treatment of these diseases. However, current inhibitors interact with a broad variety of kinases and interfere with multiple vital cellular processes, which causes toxic effects. Bioinformatics approaches that can predict inhibitor-kinase interactions from the chemical properties of the inhibitors and the kinase macromolecules might aid in design of more selective therapeutic agents, that show better efficacy and lower toxicity.</p> <p>Results</p> <p>We applied proteochemometric modelling to correlate the properties of 317 wild-type and mutated kinases and 38 inhibitors (12,046 inhibitor-kinase combinations) to the respective combination's interaction dissociation constant (K_d). We compared six approaches for description of protein kinases and several linear and non-linear correlation methods. The best performing models encoded kinase sequences with amino acid physico-chemical z-scale descriptors and used support vector machines or partial least- squares projections to latent structures for the correlations. Modelling performance was estimated by double cross-validation. The best models showed high predictive ability; the squared correlation coefficient for new kinase-inhibitor pairs ranging P²= 0.67-0.73; for new kinases it ranged P²_kin= 0.65-0.70. Models could also separate interacting from non-interacting inhibitor-kinase pairs with high sensitivity and specificity; the areas under the ROC curves ranging AUC = 0.92-0.93. We also investigated the relationship between the number of protein kinases in the dataset and the modelling results. Using only 10% of all data still a valid model was obtained with P²= 0.47, P²_kin= 0.42 and AUC = 0.83.</p> <p>Conclusions</p> <p>Our results strongly support the applicability of proteochemometrics for kinome-wide interaction modelling. Proteochemometrics might be used to speed-up identification and optimization of protein kinase targeted and multi-targeted inhibitors.</p

The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice

<p>Abstract</p> <p>Background</p> <p>Obesity and insulin resistance are two major risk factors underlying the metabolic syndrome. The development of these metabolic disorders is frequently studied, but mainly in liver, skeletal muscle, and adipose tissue. To gain more insight in the role of the small intestine in development of obesity and insulin resistance, dietary fat-induced differential gene expression was determined along the longitudinal axis of small intestines of C57BL/6J mice.</p> <p>Methods</p> <p>Male C57BL/6J mice were fed a low-fat or a high-fat diet that mimicked the fatty acid composition of a Western-style human diet. After 2, 4 and 8 weeks of diet intervention small intestines were isolated and divided in three equal parts. Differential gene expression was determined in mucosal scrapings using Mouse genome 430 2.0 arrays.</p> <p>Results</p> <p>The high-fat diet significantly increased body weight and decreased oral glucose tolerance, indicating insulin resistance. Microarray analysis showed that dietary fat had the most pronounced effect on differential gene expression in the middle part of the small intestine. By overrepresentation analysis we found that the most modulated biological processes on a high-fat diet were related to lipid metabolism, cell cycle and inflammation. Our results further indicated that the nuclear receptors Ppars, Lxrs and Fxr play an important regulatory role in the response of the small intestine to the high-fat diet. Next to these more local dietary fat effects, a secretome analysis revealed differential gene expression of secreted proteins, such as Il18, Fgf15, Mif, Igfbp3 and Angptl4. Finally, we linked the fat-induced molecular changes in the small intestine to development of obesity and insulin resistance.</p> <p>Conclusion</p> <p>During dietary fat-induced development of obesity and insulin resistance, we found substantial changes in gene expression in the small intestine, indicating modulations of biological processes, especially related to lipid metabolism. Moreover, we found differential expression of potential signaling molecules that can provoke systemic effects in peripheral organs by influencing their metabolic homeostasis. Many of these fat-modulated genes could be linked to obesity and/or insulin resistance. Together, our data provided various leads for a causal role of the small intestine in the etiology of obesity and/or insulin resistance.</p

Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail

Reproducibility of $\textit{in vivo}$ research using the mouse as a model organism depends on many factors, including experimental design, strain or stock, experimental protocols, and methods of data evaluation. Gross and histopathology are often the endpoints of such research and there is increasing concern about the accuracy and reproducibility of diagnoses in the literature. To reproduce histopathological results, the pathology protocol, including necropsy methods and slide preparation, should be followed by interpretation of the slides by a pathologist familiar with reading mouse slides and familiar with the consensus medical nomenclature used in mouse pathology. Likewise, it is important that pathologists are consulted as reviewers of manuscripts where histopathology is a key part of the investigation. The absence of pathology expertise in planning, executing and reviewing $\textit{in vivo}$ research using mice leads to questionable pathology-based findings and conclusions from studies, even in high-impact journals. We discuss the various aspects of this problem, give some examples from the literature and suggest solutions.This work was supported in part by US National Institutes of Health grants R01 AR049288, CA089713 and R21 AR063781 (to J.P.S.) and by The Warden and Fellows of Robinson College, Cambridge (to P.N.S.)

Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium