Chromosomal Instability by Inefficient Mps1 Auto-Activation Due to a Weakened Mitotic Checkpoint and Lagging Chromosomes

BACKGROUND: Chromosomal instability (CIN), a feature widely shared by cells from solid tumors, is caused by occasional chromosome missegregations during cell division. Two of the causes of CIN are weakened mitotic checkpoint signaling and persistent merotelic attachments that result in lagging chromosomes during anaphase. PRINCIPAL FINDINGS: Here we identify an autophosphorylation event on Mps1 that is required to prevent these two causes of CIN. Mps1 is phosphorylated in mitotic cells on at least 7 residues, 4 of which by autophosphorylation. One of these, T676, resides in the activation loop of the kinase domain and a mutant that cannot be phosphorylated on T676 is less active than wild-type Mps1 but is not kinase-dead. Strikingly, cells in which endogenous Mps1 was replaced with this mutant are viable but missegregate chromosomes frequently. Anaphase is initiated in the presence of misaligned and lagging chromosomes, indicative of a weakened checkpoint and persistent merotelic attachments, respectively. CONCLUSIONS/SIGNIFICANCE: We propose that full activity of Mps1 is essential for maintaining chromosomal stability by allowing resolution of merotelic attachments and to ensure that single kinetochores achieve the strength of checkpoint signaling sufficient to prevent premature anaphase onset and chromosomal instability. To our knowledge, phosphorylation of T676 on Mps1 is the first post-translational modification in human cells of which the absence causes checkpoint weakening and CIN without affecting cell viability

p68/DdX5 supports β-Catenin & RNAP II during androgen receptor mediated transcription in prostate cancer

The DEAD box RNA helicase p68 (Ddx5) is an important androgen receptor (AR) transcriptional co-activator in prostate cancer (PCa) and is over-expressed in late stage disease. β-Catenin is a multifunctional protein with important structural and signalling functions which is up-regulated in PCa and similar to p68, interacts with the AR to co-activate expression of AR target genes. Importantly, p68 forms complexes with nuclear β-Catenin and promotes gene transcription in colon cancer indicating a functional interplay between these two proteins in cancer progression. In this study, we explore the relationship of p68 and β-Catenin in PCa to assess their potential co-operation in AR-dependent gene expression, which may be of importance in the development of castrate resistant prostate cancer (CRPCa). We use immunoprecipitation to demonstrate a novel interaction between p68 and β-Catenin in the nucleus of PCa cells, which is androgen dependent in LNCaP cells but androgen independent in a hormone refractory derivative of the same cell line (representative of the CRPCa disease type). Enhanced AR activity is seen in androgen-dependent luciferase reporter assays upon transient co-transfection of p68 and β-Catenin as an additive effect, and p68-depleted Chromatin-Immunoprecipitation (ChIP) showed a decrease in the recruitment of the AR and β-Catenin to androgen responsive promoter regions. In addition, we found p68 immunoprecipitated with the processive and non-processive form of RNA polymerase II (RNAP II) and show p68 recruited to elongating regions of the AR mediated PSA gene, suggesting a role for p68 in facilitating RNAP II transcription of AR mediated genes. These results suggest p68 is important in facilitating β-Catenin and AR transcriptional activity in PCa cells

Consistency and flexibility in solving spatial tasks: different horses show different cognitive styles

Individual animals vary in their behaviour and reactions to novel situations. These differences may extend to differences in cognition among individuals. We tested twenty-six horses for their ability to detour around symmetric and asymmetric obstacles. All of the animals were able to get around the barrier to reach a food target, but varied in their approach. Some horses moved slowly but were more accurate in choosing the shortest way. Other horses acted quickly, consistently detoured in the same direction, and did not reliably choose the shortest way. The remaining horses shifted from a faster, directionally consistent response with the symmetric barrier, to a slower but more accurate response with the asymmetric barrier. The asymmetric barrier induced a reduction in heart rate variability, suggesting that this is a more demanding task. The different approaches used to solve the asymmetric task may reflect distinct cognitive styles in horses, which vary among individuals, and could be linked to different personality traits. Understanding equine behaviour and cognition can inform horse welfare and management

Emerging antitrust threats and enforcement actions in the online world

In recent years, our online markets and data-driven economy have delivered waves of innovation and efficiencies to the benefit of us all. And yet, in recent years an increased realisation has emerged as to the limitations of this competitive landscape and the power of markets to correct themselves. Network effects, increased concentration, personalised dynamic algorithmic pricing and contractual restrictions, have turned the online environment to less than perfect. In this paper, we consider three key antitrust threats - algorithmic collusion, price discrimination, and the rise of the super-platforms – and explore enforcement action they may call for

Online Platforms and the EU Digital Single Market

Our submission to the U.K. House of Lords, Internal Market Sub-Committee is based on our joint research, which explores the effects Big Data and technology have on competition dynamics. It reviews the use of technology to facilitate collusion, conscious parallelism, and unilateral price discrimination as well as the effects of online and mobile platforms. Our submission addresses the following issues: ? What role does data play in the business model of online platforms? ? Can data-driven online platforms have excessive market power? ? If so, how can they abuse this power? ? If so, how does this happen and what effect does it create? ? Is European competition law able adequately to address abuse by online platforms

Two artificial neural networks meet in an online hub and change the future (Of competition, market dynamics and society)

In the future, one may imagine a new breed on antitrust humor. Jokes might start along the following lines: “Two Artificial Neural Network and one Nash equilibrium meet in an online (pub) hub. After a few milliseconds, a unique silent friendship is formed…”Back to the present; we are not sure how this joke might end. Nor can we estimate how funny future consumers would find it. We can, however, explain, at present, how technological advancements have changed, and will continue to change, the dynamics of competition and subsequently the distribution of wealth is society. How algorithms may be used in stealth mode to stabilize and dampen market competition while retaining the façade of competitive environment. That tale is at the heart of this paper.</p

How your digital helper may undermine your welfare, and our democracy

Digital assistants embody the dream of an effortless future, free from the shackles of yesteryear. A tool which caters for users’ our needs, excels at anticipating their our wants and delivers a personalized online environment. While digital assistants can certainly offer great value, a closer look reveals how in an algorithm and data driven world, one’s your digital assistant may ultimately serve the interests of others. It may be used to establish ed a controlled and manipulated personalized environment in which competition, welfare, privacy and democracy give way to corporate interests. The future is not necessarily bleak, but requires our attention if we want these assistants it to match the our euphoric effortless dream

Looking up in the data-driven economy

How competitive is our market economy? Not as much as it ought to be. And the growth of big data threatens to make things even worse. Antitrust regulators already struggle to keep markets competitive. How will they fare in economies increasingly dominated by a few super-platforms