Magnetohydrodynamic relaxation of AGN ejecta: radio bubbles in the intracluster medium

X-ray images of galaxy clusters often display underdense bubbles which are apparently inflated by AGN outflow. I consider the evolution of the magnetic field inside such a bubble, using a mixture of analytic and numerical methods. It is found that the field relaxes into an equilibrium filling the entire volume of the bubble. The timescale on which this happens depends critically on the magnetisation and helicity of the outflow as well as on properties of the surrounding ICM. If the outflow is strongly magnetised, the magnetic field undergoes reconnection on a short timescale, magnetic energy being converted into heat whilst the characteristic length scale of the field rises; this process stops when a global equilibrium is reached. The strength of the equilibrium field is determined by the magnetic helicity injected into the bubble by the AGN: if the outflow has a consistent net flux and consequently a large helicity then a global equilibrium will be reached on a short timescale, whereas a low-helicity outflow results in no global equilibrium being reached and at the time of observation reconnection will be ongoing. However, localised flux-tube equilibria will form. If, on the other hand, the outflow is very weakly magnetised, no reconnection occurs and the magnetic field inside the bubble remains small-scale and passive. These results have implications for the internal composition of the bubbles, their interaction with ICM -- in particular to explain how bubbles could move a large distance through the ICM without breaking up -- as well as for the cooling flow problem in general. In addition, reconnection sites in a bubble could be a convenient source of energetic particles, circumventing the problem of synchrotron emitters having a shorter lifetime than the age of the bubble they inhabit.Comment: MNRAS accepted. 15 pages, 10 figures

Getting a Transcription Factor to Only One Nucleus Following Mitosis

The Ace2 transcription factor from budding yeast has both a regulated nuclear localization signal and a regulated nuclear export signal, and Ace2 phosphorylation by the Cbk1 kinase results in Ace2 accumulation in daughter cells but not mothers

Pauli's Principle in Probe Microscopy

Exceptionally clear images of intramolecular structure can be attained in dynamic force microscopy through the combination of a passivated tip apex and operation in what has become known as the "Pauli exclusion regime" of the tip-sample interaction. We discuss, from an experimentalist's perspective, a number of aspects of the exclusion principle which underpin this ability to achieve submolecular resolution. Our particular focus is on the origins, history, and interpretation of Pauli's principle in the context of interatomic and intermolecular interactions.Comment: This is a chapter from "Imaging and Manipulation of Adsorbates using Dynamic Force Microscopy", a book which is part of the "Advances in Atom and Single Molecule Machines" series published by Springer [http://www.springer.com/series/10425]. To be published late 201

MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53

SummaryThe MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53

Computational Methodologies and Physical Insights into Electronic Energy Transfer in Photosynthetic Light-Harvesting Complexes

We examine computational techniques and methodologies currently in use to explore electronic excitation energy transfer in the context of light-harvesting complexes in photosynthetic antenna systems, and comment on some new insights into the underlying physics. Advantages and pitfalls of these methodologies are discussed, as are some physical insights into the photosynthetic dynamics. By combining results from molecular modelling of the complexes (structural description) with an effective non-equilibrium statistical description (time evolution), we identify some general features, regardless of the particular distribution in the protein scaffold, that are central to light-harvesting dynamics and, that could ultimately be related to the high efficiency of the overall process. Based on these general common features, some possible new directions in the field are discussed.Comment: Invited Perspective Article for Phys. Chem. Chem. Phy

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis.

The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents

The human keratins: biology and pathology

The keratins are the typical intermediate filament proteins of epithelia, showing an outstanding degree of molecular diversity. Heteropolymeric filaments are formed by pairing of type I and type II molecules. In humans 54 functional keratin genes exist. They are expressed in highly specific patterns related to the epithelial type and stage of cellular differentiation. About half of all keratins—including numerous keratins characterized only recently—are restricted to the various compartments of hair follicles. As part of the epithelial cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, some keratins also have regulatory functions and are involved in intracellular signaling pathways, e.g. protection from stress, wound healing, and apoptosis. Applying the new consensus nomenclature, this article summarizes, for all human keratins, their cell type and tissue distribution and their functional significance in relation to transgenic mouse models and human hereditary keratin diseases. Furthermore, since keratins also exhibit characteristic expression patterns in human tumors, several of them (notably K5, K7, K8/K18, K19, and K20) have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping. Future research might open further fields of clinical application for this remarkable protein family

Environment and Obesity in the National Children’s Study

Objective: In this review we describe the approach taken by the National Children’s Study (NCS), a 21-year prospective study of 100,000 American children, to understanding the role of environmental factors in the development of obesity. Data sources and extraction: We review the literature with regard to the two core hypotheses in the NCS that relate to environmental origins of obesity and describe strategies that will be used to test each hypothesis. Data synthesis: Although it is clear that obesity in an individual results from an imbalance between energy intake and expenditure, control of the obesity epidemic will require understanding of factors in the modern built environment and chemical exposures that may have the capacity to disrupt the link between energy intake and expenditure. The NCS is the largest prospective birth cohort study ever undertaken in the United States that is explicitly designed to seek information on the environmental causes of pediatric disease. Conclusions: Through its embrace of the life-course approach to epidemiology, the NCS will be able to study the origins of obesity from preconception through late adolescence, including factors ranging from genetic inheritance to individual behaviors to the social, built, and natural environment and chemical exposures. It will have sufficient statistical power to examine interactions among these multiple influences, including gene–environment and gene–obesity interactions. A major secondary benefit will derive from the banking of specimens for future analysis

Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen

SummaryBoth hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1α and nuclear factor (NF)-κB, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1α accumulation requires NF-κB signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1α accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1α degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or α-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-κB-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1α accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron)

The neurobiology of attention deficit/hyperactivity disorder.

ADHD is a brain based disorder with structural and functional abnormalities in widespread but specific areas of the brain. The most significant and consistent structural imaging findings include smaller total brain volumes, and reduced volumes in the right frontal lobe, right parietal cortex, caudate nucleus, cerebellar hemispheres, and posterior-inferior lobules of the cerebellar vermis. ADHD involves hypofunction of catecholaminergic circuits, particularly those that project to the prefrontal cortex. A minimum of 18 genes have been reported to be associated with the disorder; among them the DRD4 7-repeat allele has been found associated with a thinner prefrontal and posterior parietal cortex. Epigenetic factors acting during critical periods of prenatal and postnatal development may interact with genetic determinants. Methylphenidate, as well as the catecholaminergic nonstimulant atomoxetine, are effective in improving ADHD symptoms