Role of Tip60 tumor suppressor in DNA repair pathway

To prevent the damage caused by DNA strand breaks, eukaryotic cells have evolved a series of highly conserved DNA repair mechanisms. The ubiquitously expressed acetyltransferase, Tip60, plays a central role in ATM (ataxia-telangiectasia mutated) activation which is involved in DNA repair. Recent work uncovered a new mechanism of ATM activation mediated by Tip60 and demonstrated that histone methylation, specifically, trimethylation of histone H3, is a key factor in the process. Here, we review the current understanding of how Tip60 is activated and how it activates ATM in response to DNA damage.     

The Applicability of Mathematics as a Philosophical Problem: Mathematization as Exploration

This paper discerns two types of mathematization, a foundational and an explorative one. The foundational perspective is well-established, but we argue that the explorative type is essential when approaching the problem of applicability and how it influences our conception of mathematics. The first part of the paper argues that a philosophical transformation made explorative mathematization possible. This transformation took place in early modernity when sense acquired partial independence from reference. The second part of the paper discusses a series of examples from the history of mathematics that highlight the complementary nature of the foundational and exploratory types of mathematization.     

The Perspective of the Instruments: Mediating Collectivity

Numerous studies in the fields of Science and Technology Studies (STS) and philosophy of technology have repeatedly stressed that scientific practices are collective practices that crucially depend on the presence of scientific technologies. Postphenomenology is one of the movements that aims to draw philosophical conclusions from these observations through an analysis of human–technology interactions in scientific practice. Two other attempts that try to integrate these insights into philosophy of science are Ronald Giere’s Scientific Perspectivism (2006) and Davis Baird’s Thing Knowledge (2004). In this paper, these two approaches will be critically discussed from the perspective of postphenomenology. We will argue that Giere and Baird problematically assume that scientific instruments (a) have a determined function, and (b) that all human members of a scientific collective have immediate access to this function. However, these assumptions also allow them to offer a clear answer to the question how scientists can collectively relate to scientific phenomena. Such an answer is not yet (explicitly) formulated within the postphenomenological perspective. By adding a postphenomenological touch to the semiotic approach in Actor-Network Theory, we offer an account of how different individual human–technology relations are integrated into larger scientific collectives. We do so by showing that scientific instruments not only help constitute scientific phenomena, but also the intersubjectivity within such collectives.     

Quantum Theory and the Nature of Consciousness

Our interest focusses on the idea, that consciousness is a powerful acting entity. Up to now there does not exist a scientific concept for this idea. This is not due to problems within the field of psychology or brain research, but rather in resisting theories of modern physics. That is, why we have to search for a solution in the field of physics. A solution can be found in a new understanding of the basics of physical theory. That could be given by abstract and absolute quantum bits of information (AQI bits). To avoid the popular misunderstanding of “information” as “meaningful” it was necessary to find a new word for the free-of-meaning AQI bits: the AQI bits establish a quantum pre-structure termed “Protyposis” (Greek: “pre-formation”), out of which real objects can be formed, starting from energetical and material elementary particles. The Protyposis AQI bits provide a pre-structure for all entities in natural sciences. They are the basic entities, whereof the physical nature of the brain, on the one hand, and the mental nature of consciousness, on the other hand, were formed during the cosmological and the following biological evolution. A deeper understanding of quantum structures may help to overcome the resistance against quantum theory in the field of brain research and consciousness. The key for an understanding is the concept of Protyposis, which means an abstract quantum information free of any definite meaning. With the AQI bits of the Protyposis, both, massless and massive quantum particles can be constructed. Even quantum information with special meanings, in example grammatically formulated thoughts, eventually could be explained. As long as the fundamental basis of quantum theory is misunderstood as being formed by a manifold of some small objects like atoms, quarks, or strings, the problem of understanding consciousness has no solution. If instead we understand quantum theory as based on truly simple quantum structures, there would be no longer fundamental problems for an understanding of consciousness.     

Approximation,Mad Men and the Death of JFK

In this article I take the US television series Mad Men (2007—present) as an exemplary ‘approximation’, a term I adopt to signal the way in which certain texts construct a changeable, fluid ‘truth’ resulting from collisions, exchange and dialectical argument. Approximations are layered, their formal layerings mirroring a layered, multifaceted argument. Mad Men integrates and represents real historical events within a fictional setting, and act that suggests that an event or action can never be finished, fixed and not open to reassessment. Specifically, this article examines ‘The Grown Ups’, Episode 12 of Season 3, which charts the events of 22 November 1963, the day Kennedy was assassinated. Although we might be able to bring to mind the images and conspiracy theories that have been made available since (such Abraham Zapruder’s 8 mm home movie footage of the assassination), these images were not available at the time. Mad Men as a series always strives to represent its historical milieu as authentically as possible, so the characters re-enact 22 November 1963 as authentically as possible by watching only what was on television that day (the news bulletin, Walter Kronkite’s announcement that Kennedy is dead). The contemporary backdrop to these events, including the resonances of ‘9/11’ through Mad Men, inform and collide with the authenticity on the screen.     

The Documentary Real: Thinking Documentary Aesthetics

In this article we consider the growing interest in recent years in the use of documentary strategies in the wold of contemporary art, film and performing arts and explore some of the central epistemological assumptions underpinning the persistent idea that the documentary should be equated with ‘non-fiction’. Following Stella Bruzzi we argue that if documentary theory maintains objectivity as the primary measure of value, it will inevitably and continuously arrive at the conclusion that the documentary genre is fundamentally flawed. Instead, we propose to move beyond the ‘realist epistemology’ of documentary theory and focus on the ‘documentary real’, i.e. the specific performativity of the reality constructed in and by the documentary genre. In the last paragraphs, we introduce the various articles that address the “documentary real” in this special issue.     

The TET enzymes

During the past decade, we have learnt that the most common DNA modification, 5-methylcytosine (5mC), playing crucial roles in development and disease, is not stable but can be actively reversed to its unmodified form via enzymatic catalysis involving the TET enzymes. These ground-breaking discoveries have been achieved thanks to technological advances in the detection of the oxidized forms of 5mC and to the boldness of individual scientists. The TET enzymes require molecular oxygen for their catalysis, making them important targets for hypoxia research. They also require special cofactors which enable additional levels of regulation. Moreover, mutations and other genetic alterations in TETs are found, especially in myeloid malignances. This review focuses on the kinetic and inhibitory properties of the TET enzymes and the role of TETs in cellular differentiation and transformation and in cancer.     

Liver cell therapy: is this the end of the beginning?

The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought. Liver progenitor and pluripotent stem cells offer potential cell sources that could be used clinically. This review discusses recent approaches in liver cell transplantation and requirements to improve the process, with the ultimate goal being efficient organ regeneration. We also discuss the potential off-target effects of cell-based therapies, and the advantages and drawbacks of current pre-clinical animal models used to study organ senescence, repopulation and regeneration.     

Macropinocytosis,mTORC1 and cellular growth control

The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces initiate biochemical signals that increase anabolic metabolism and macropinocytosis, an actin-dependent endocytic process in which relatively large volumes of extracellular solutes and nutrients are internalized and delivered efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer cells, and supports the growth of cells transformed by oncogenic K-Ras. Growth factor receptor signaling and the overall metabolic status of the cell are coordinated in the cytoplasm by the mechanistic target-of-rapamycin complex-1 (mTORC1), which positively regulates protein synthesis and negatively regulates molecular salvage pathways such as autophagy. mTORC1 is activated by two distinct Ras-related small GTPases, Rag and Rheb, which associate with lysosomal membranes inside the cell. Rag recruits mTORC1 to the lysosomal surface where Rheb directly binds to and activates mTORC1. Rag is activated by both lysosomal luminal and cytosolic amino acids; Rheb activation requires phosphoinositide 3-kinase, Akt, and the tuberous sclerosis complex-1/2. Signals for activation of Rag and Rheb converge at the lysosomal membrane, and several lines of evidence support the idea that growth factor-dependent endocytosis facilitates amino acid transfer into the lysosome leading to the activation of Rag. This review summarizes evidence that growth factor-stimulated macropinocytosis is essential for amino acid-dependent activation of mTORC1, and that increased solute accumulation by macropinocytosis in transformed cells supports unchecked cell growth.