Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance.

The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC-WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt\u27s lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC-WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC-WDR5 inhibitors could be developed as anticancer agents

Lysophosphatidylcholine in phospholipase A(2)-modified LDL triggers secretion of angiopoietin 2

Background and aims: Secretory phospholipase A(2) (PLA(2)) hydrolyzes LDL phospholipids generating modified LDL particles (PLA(2)-LDL) with increased atherogenic properties. Exocytosis of Weibel-Palade bodies (WPB) releases angiopoietin 2 (Ang2) and externalizes P-selectin, which both play important roles in vascular inflammation. Here, we investigated the effects of PLA(2)-LDL on exocytosis of WPBs. Methods: Human coronary artery endothelial cells (HCAECs) were stimulated with PLA(2)-LDL, and its uptake and effect on Ang2 release, leukocyte adhesion, and intracellular calcium levels were measured. The effects of PLA(2)-LDL on Ang2 release and WPB exocytosis were measured in and ex vivo in mice. Results: Exposure of HCAECs to PLA(2)-LDL triggered Ang2 secretion and promoted leukocyte-HCAEC interaction. Lysophosphatidylcholine was identified as a critical component of PLA(2)-LDL regulating the WPB exocytosis, which was mediated by cell-surface proteoglycans, phospholipase C, intracellular calcium, and cytoskeletal remodeling. PLA(2)-LDL also induced murine endothelial WPB exocytosis in blood vessels in and ex vivo, as evidenced by secretion of Ang2 in vivo, P-selectin translocation to plasma membrane in intact endothelial cells in thoracic artery and tracheal vessels, and reduced Ang2 staining in tracheal endothelial cells. Finally, in contrast to normal human coronary arteries, in which Ang2 was present only in the endothelial layer, at sites of advanced atherosclerotic lesions, Ang2 was detected also in the intima, media, and adventitia. Conclusions: Our studies reveal PLA(2)-LDL as a potent agonist of endothelial WPB exocytosis, resulting in increased secretion of Ang2 and translocation of P-selectin. The results provide mechanistic insight into PLA(2)-LDL-dependent promotion of vascular inflammation and atherosclerosis.Peer reviewe

Streptococcus pneumoniae pneumolysin and neuraminidase A convert high-density lipoproteins into pro-atherogenic particles

High-density lipoproteins (HDLs) are a group of different subpopulations of sialylated particles that have an essential role in the reverse cholesterol transport (RCT) pathway. Importantly, changes in the protein and lipid composition of HDLsmay lead to the formation of particles with reduced atheroprotective properties. Here, we show that Streptococcus pneumoniae pneumolysin (PLY) and neuraminidase A (NanA) impair HDL function by causing chemical and structural modifications of HDLs. The proteomic, lipidomic, cellular, and biochemical analysis revealed that PLY and NanA induce significant changes in sialic acid, protein, and lipid compositions of HDL. The modified HDL particles have reduced cholesterol acceptor potential from activated macrophages, elevated levels of malondialdehyde adducts, and show significantly increased complement activating capacity. These results suggest that accumulation of these modified HDL particles in the arterial intima may present a trigger for complement activation, inflammatory response, and thereby promote atherogenic disease progression.Peer reviewe

The optical behaviour of BL Lacertae at its maximum brightness levels: a blend of geometry and energetics

In 2021 BL Lacertae underwent an extraordinary activity phase, which was intensively followed by the Whole Earth Blazar Telescope (WEBT) Collaboration. We present the WEBT optical data in the BVRI bands acquired at 36 observatories around the world. In mid 2021 the source showed its historical maximum, with R = 11.14. The light curves display many episodes of intraday variability, whose amplitude increases with source brightness, in agreement with a geometrical interpretation of the long-term flux behaviour. This is also supported by the long-term spectral variability, with an almost achromatic trend with brightness. In contrast, short-term variations are found to be strongly chromatic and are ascribed to energetic processes in the jet. We also analyse the optical polarimetric behaviour, finding evidence of a strong correlation between the intrinsic fast variations in flux density and those in polarisation degree, with a time delay of about 13 h. This suggests a common physical origin. The overall behaviour of the source can be interpreted as the result of two mechanisms: variability on time scales greater than several days is likely produced by orientation effects, while either shock waves propagating in the jet, or magnetic reconnection, possibly induced by kink instabilities in the jet, can explain variability on shorter time scales. The latter scenario could also account for the appearance of quasi-periodic oscillations, with periods from a few days to a few hours, during outbursts, when the jet is more closely aligned with our line of sight and the time scales are shortened by relativistic effects.Comment: 15 pages, 16 figures, submitted to MNRA

In, Against and Beyond Precarity: Work in Insecure Times

In this Foreword to the special issue ‘In, Against and Beyond Precarity’ the guest editors take stock of the existing literature on precarity, highlighting the strengths and limitations of using this concept as an analytical tool for examining the world of work. Concluding that the overstretched nature of concept has diluted its political effectiveness, the editors suggest instead a focus on precarization as a process, drawing from perspectives that focus on the objective conditions, as well as subjective and heterogeneous experiences and perceptions of insecure employment. Framed in this way, they present a summary of the contributions to the special issue spanning a range of countries and organizational contexts, identifying key drivers, patterns and forms of precarization. These are conceptualized as implicit, explicit, productive and citizenship precarization. These forms and patterns indicate the need to address precariousness in the realm of social reproduction and post-wage politics, while holding these in tension with conflicts at the point of production. Finally, the guest editors argue for a dramatic re-think of current forms of state and non-state social protections as responses to the precarization of work and employment across countries in both the Global ‘North’ and ‘South’

The values of liberté, égalité, fraternité fifty years on: why the 'free speech' debate makes it even less likely that Mai '68 could happen in Britain now than it was then

In May 1968 there was a strong sense of left-wing camaraderie that drew many French university students into collaboration with the workers’ unions to rise up against de Gaulle’s government. It is highly unlikely that British campuses could be gripped by these values of solidarity and shared agency in a common cause: what can that tell us about Britain? In Britain there are assumptions on the part of many young adults that we are free, equal and fraternal. The parallel digital world that they inhabit so comfortably appears to encourage and facilitate consumer behaviour and freedom of expression: it seems possible to buy and write online almost exactly what you like without consequences. Yet against a backdrop of crass populist discourse there are urgent issues regarding ethical behaviour: online and offline use of language is sharply racialised and gendered. People of colour and women of all ages are frequently attacked. Hate speech is poorly controlled and legal restraints are lagging behind the global digital empires. In addition, on campus the British government is intervening much more than ever before, which makes some students less free, less equal and less fraternal than others. Free speech is being constrained. Populism is on the rise, framed by political alienation. Finally, precarity affects the young in their responses to university: is it worth incurring the debt of high fees? The philosophy of Ricoeur and Lorey show how to interrogate dominant discourses and attempt a better world

Differential activation of the lateral premotor cortex during action observation

<p>Abstract</p> <p>Background</p> <p>Action observation leads to neural activation of the human premotor cortex. This study examined how the level of motor expertise (expert vs. novice) in ballroom dancing and the visual viewpoint (internal vs. external viewpoint) influence this activation within different parts of this area of the brain.</p> <p>Results</p> <p>Sixteen dance experts and 16 novices observed ballroom dance videos from internal or external viewpoints while lying in a functional magnetic resonance imaging scanner. A conjunction analysis of all observation conditions showed that action observation activated distinct networks of premotor, parietal, and cerebellar structures. Experts revealed increased activation in the ventral premotor cortex compared to novices. An internal viewpoint led to higher activation of the dorsal premotor cortex.</p> <p>Conclusions</p> <p>The present results suggest that the ventral and dorsal premotor cortex adopt differential roles during action observation depending on the level of motor expertise and the viewpoint.</p