Components of the ubiquitin-proteasome pathway compete for surfaces on Rad23 family proteins

Background: The delivery of ubiquitinated proteins to the proteasome for degradation is a key step in the regulation of the ubiquitin-proteasome pathway, yet the mechanisms underlying this step are not understood in detail. The Rad23 family of proteins is known to bind ubiquitinated proteins through its two ubiquitin-associated (UBA) domains, and may participate in the delivery of ubiquitinated proteins to the proteasome through docking via the Rad23 ubiquitin-like (UBL) domain. Results: In this study, we investigate how the interaction between the UBL and UBA domains may modulate ubiquitin recognition and the delivery of ubiquitinated proteins to the proteasome by autoinhibition. We have explored a competitive binding model using specific mutations in the UBL domain. Disrupting the intramolecular UBL-UBA domain interactions in HHR23A indeed potentiates ubiquitin-binding. Additionally, the analogous surface on the Rad23 UBL domain overlaps with that required for interaction with both proteasomes and the ubiquitin ligase Ufd2. We have found that mutation of residues on this surface affects the ability of Rad23 to deliver ubiquitinated proteins to the proteasome. Conclusions: We conclude that the competition of ubiquitin-proteasome pathway components for surfaces on Rad23 is important for the role of the Rad23 family proteins in proteasomal targeting

Helicity and alpha-effect by current-driven instabilities of helical magnetic fields

Helical magnetic background fields with adjustable pitch angle are imposed on a conducting fluid in a differentially rotating cylindrical container. The small-scale kinetic and current helicities are calculated for various field geometries, and shown to have the opposite sign as the helicity of the large-scale field. These helicities and also the corresponding $\alpha$-effect scale with the current helicity of the background field. The $\alpha$-tensor is highly anisotropic as the components $\alpha_{\phi\phi}$ and $\alpha_{zz}$ have opposite signs. The amplitudes of the azimuthal $\alpha$-effect computed with the cylindrical 3D MHD code are so small that the operation of an $\alpha\Omega$ dynamo on the basis of the current-driven, kink-type instabilities of toroidal fields is highly questionable. In any case the low value of the $\alpha$-effect would lead to very long growth times of a dynamo in the radiation zone of the Sun and early-type stars of the order of mega-years.Comment: 6 pages, 7 figures, submitted to MNRA

Self-Pulsating Semiconductor Lasers: Theory and Experiment

We report detailed measurements of the pump-current dependency of the self-pulsating frequency of semiconductor CD lasers. A distinct kink in this dependence is found and explained using rate-equation model. The kink denotes a transition between a region where the self-pulsations are weakly sustained relaxation oscillations and a region where Q-switching takes place. Simulations show that spontaneous emission noise plays a crucial role for the cross-over.Comment: Revtex, 16 pages, 7 figure

Continuous 25-yr aerosol records at coastal Antarctica: Part 2: Variability of the radionuclides 7Be, 10Be 210Pb

We investigated the variability of210Pb,7Be10Be in coastal Antarctic aerosol samples based on continuous, monthly annually resolved time series obtained from Neumayer Station over the period 1983 to 2008. Clear seasonal cycles peaking in the local summe

Overcoming of Information Extremism as a Condition of Human and Social Wellbeing

The urgency of this research is indisputable because the subjects of information extremism having at their disposal various mass media can disseminate their beliefs and ideas over thousands of people in different countries all over the world. International collaboration is needed to struggle against this evil. The paper provides deep insight into the notion "information extremism", as well as its classification and forms. It is aimed at revealing the specific character of the notions "information extremism" and "information terrorism" and their investigation. Illocutionary influence as the major method of information extremism is highlighted in the paper. The authors demonstrate important influence of mass media including the Internet over readership, especially the youth. It is concluded that the issue of information extremism requires for more rigorous and deeper consideration. It is necessary to fight against forms of its manifestation, because they have a significant effect on homeland and international safety and stability

The Spectral Dimension of Arctic Outgoing Longwave Radiation and Greenhouse Efficiency Trends From 2003 to 2016

Fourteen years of spectral fluxes derived from collocated Atmospheric Infrared Sounder (AIRS) and Clouds and the Earth’s Radiant Energy System (CERES) observations are used in conjunction with AIRS retrievals to examine the trends of zonal mean spectral outgoing longwave radiation (OLR) and greenhouse efficiency (GHE) in the Arctic. AIRS retrieved profiles are fed into a radiative transfer model to generate synthetic clear‐sky spectral OLR. Trends are derived from the simulated clear‐sky spectral OLR and GHE and then compared with their counterparts derived from collocated observations. Spectral trends in different seasons are distinctively different. March and September exhibit positive trends in spectral OLR over the far‐IR dirty window and mid‐IR window region for most of the Arctic. In contrast, spectral OLR trends in July are negative over the far‐IR dirty window and can be positive or negative in the mid‐IR window depending on the latitude. Sensitivity studies reveal that surface temperature contributes much more than atmospheric temperature and humidity to the spectral OLR and GHE trends, while the contributions from the latter two are also discernible over many spectral regions (e.g., trends in the far‐IR dirty window in March). The largest increase of spectral GHE is seen north of 80°N in March across the water vapor v2 band and far‐IR. When the secular fractional change of spectral OLR is less than that of surface spectral emission, an increase of spectral GHE can be expected. Spectral trend analyses reveal more information than broadband trend analyses alone.Key PointsObserved Arctic zonal mean trends of spectral flux and greenhouse efficiency are studied for the first timeSpectral trends are seasonally dependent and reveal more information than broadband trendsChanges in surface temperature contribute the most to overall spectral trends, but changes due to air temperature and humidity trends are discerniblePeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151304/1/jgrd55648_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151304/2/jgrd55648.pd

Systems biology and cancer, [Editorial]

The systems approach to complex biological problems has rapidly gained ground during the first decade of this century. There are several reasons for this development. An important one is that while the achievement of sequencing the complete human genome, and those of other species, has been of great benefit to fundamental science, for example in comparative genomics and evolutionary biology, it has not led to the expected quick and simple solutions to multifactorial diseases (2010). On the contrary, cancer, cardiovascular, respiratory, metabolic and nervous diseases have all been resistant to reductionist analysis. In the case of cancer the hope that by identifying what are called oncogenes we would not only understand cancer but be led naturally to its cure has not been fulfilled ([Sonnenschein and Soto, 1999] and [Sonnenschein and Soto, 2011]). In all areas of medical science, despite the identification of hundreds more potential targets by genome sequencing, the pharmaceutical industry has been faced with a decline in the production of new successful drugs. The more we find out about the fundamental elements of biology, the DNA, RNAs, proteins, metabolites, membrane systems, organelles, the more puzzling the picture becomes. Even central biological concepts, like that of a gene, have changed and have even become difficult to define (Beurton et al., 2008 In: P.J. Beurton, R. Falk and H.-J. Rheinberger, Editors, The Concept of the Gene in Development and Evolution: Historical and Epistemological Perspectives, Cambridge University Press, Cambridge (2008).Beurton et al., 2008).\ud \ud Reassessment of the fundamental concepts of biological science is therefore necessary. This is happening in all fields, including genetics (Beurton et al., 2008), evolution ([Pigliucci and Müller, 2010], [Gissis and Jablonka, 2011] and [Shapiro, 2011]), cancer (Soto et al., 2008), development and the relationships between genomes and phenotypes ([Noble, 2011b] and [Noble, 2011a]). What once were heresies seem to be creeping back into mainstream biology.\ud \ud One of the driving forces of this development is the use of mathematical modelling in systems biology. This has brought a rigorous quantitative approach to what otherwise would be largely untestable theories. Mathematical models provide a framework in which to interpret the vast amount of experimental data generated on a daily basis and to suggest subsequent experiments necessary to test theories. The traditional verbal reasoning approach is not appropriate in many cases due to the complexity of biology (Gatenby and Maini, 2003) which renders intuition insufficient as results are often counter-intuitive, a characteristic outcome of scientific research that goes as far back as Copernicus’ proposal of an heliocentric planetary system. This vast complexity requires a mathematical approach.\ud \ud The motivation for this focussed issue of the journal is that the field of cancer is ripe for the systems biology approach. As editors we have collected an eclectic mix of articles. This is not a ‘one view fits all’ approach. It is rather one to ‘let a hundred flowers bloom’. At this stage in our understanding we cannot be sure where the next big insights are going to come from.\ud \ud Since the 18th century biologists and philosophers tried to define the place of biology1 in science and in particular its relationship with physics. A two hundred year debate followed, with biologists adopting “physicalist” or “vitalistic” stands. Was life to be explained in a totally materialistic way by the laws of physics? Or were there additional “forces” present in the living matter but absent in the inert one? Curiously, as vitalism dwindled among biologists in the 20th century, physicists like Schrödinger (1944) and Elsasser (1987) were the ones that tried to understand biological order and were prepared to find new laws that applied only to living matter.2 No new laws resulted from this search, but from the emerging field of information theories, biologists adopted information as the metaphor for the study of biological organization.3 This, however, has not produced the desired effects either, probably because the attempts to formalize this approach failed, which in turn suggests that it was conceptually wrong. Can biology achieve formalization through mathematics, a feat that physics has accomplished so successfully?\ud \ud The article by Giuseppe Longo and Mael Montevil (2011) (mathematicians), analyzes the principles of intelligibility in physics, which is based on symmetries, and posit that the role of symmetries in biology is different: in their words “the permanent change of symmetries …per se modifies the analysis of the internal and external processes of life, both in ontogenesis and evolution”. They propose to consider the roles played by local and global symmetry changes, along extended critical transitions. According to them, the mathematization of this state of extended criticality may provide the adequate frame to understand biological complexity. Paul-Antoine Miquel (2011) (a philosopher), reflects on the philosophical aspects of the theoretical analysis by Longo and Montevil and concludes that “the philosophical key point for us is that they (Longo and Montevil) interpret this mathematical space in which anti-entropy is realized in biological criticality as an extension of the classical physical theoretical frameworks.” These two contributions aim at improving our understanding on why the principles governing living organisms are different from those defining the physicality of inanimate objects and provide a conceptual frame of reference and a point of departure for constructing a mathematics for biology.\ud \ud Stuart Baker (a bio-statistician) and Barnett Kramer (a cancer epidemiologist) (2011) evaluate the potential contributions of different approaches to Systems Biology when applied to uncover buried messages in the genesis of cancer which may set new trends in research and in ways to benefit patients. They anticipate both promises and perils in applying systems biology to cancer. The great promise of systems biology comes from the idea that studying a system can provide information not available by separately studying the workings of each part. However, they perceive a divide between systems biology based on the principles of biology or biophysics, systems biology related to statistics, bioinformatics, and reverse engineering, and systems biology involving clinical predictions, sometimes without full appreciation of other viewpoints. The peril comes when the rules leading to a complex system vary over many components and the sample sizes are limited for identifying the rules and making predictions. Baker et al. have introduced the concept of “paradigm instability” when referring to current state of affairs through which the field of cancer research is traversing. Thus, they focus on a number of paradoxes that exist in this field and cautiously point at ways that might increase knowledge about the disease and also benefit patients.\ud \ud Simon Rosenfeld (2011) (a mathematical physicist) makes a critical analysis of the assumptions and concepts used in the emerging field of network biology, particularly those on the actual physics and chemistry happening inside cells. He posits that, in biology there is dual causality, that is, in addition to the constraints imposed by the laws of nature, there is the evolutionary history of the organism: “…inherent dynamical instability represents the natural laws and physico-chemical principles whereas biological robustness is the result of evolutionary history in which this dynamical instability has been effectively used for gaining evolutionary advantages and survival.” He subscribes to the notion that “Mathematics represents a systematic and orderly way of describing and organizing knowledge. In the majority of scientific disciplines, mathematical reasoning has proven to be an unparalleled and indispensable tool for understanding complex dynamics.” He forcefully argues for adopting a Systems Biology approach to resolve complex biological problems while complying with a comprehensive evolutionary perspective.\ud \ud Plankar et al. (2011) challenge the genetically determined paradigm of cancer from another angle to characterise cancer as the result of impaired coherence leading to progressive destabilisation of molecular and gene regulatory networks. As they write in their conclusion “It is becoming clear that even with potentially unlimited insight into the dynamics of genetic changes, cancer could not be sufficiently explained, and neither could it be explained in terms of separate linear molecular pathways alone. During the last decade, scientific attention has turned dramatically towards the metabolic, bioenergetic, developmental, and systems biology aspects of cancer, reflecting a gradual paradigm shift towards its non-genetic origin.”\ud \ud Enderling and Hahnfeldt (2011) analyse the dynamics of a growing solid tumour composed of cancer stem cells and cancer non-stem cells using a simple hybrid cellular automaton (CA) model. They illustrate the counter-intuitive finding that increasing the rate of apoptosis, while obviously reducing tumour size in the short-term, actually enhances growth in the long-term. They show that tumours can remain dormant for a long time but stimulation of apoptosis can cause the tumour cell population to aggressively invade. Their work suggests that the widely regarded “evading cell death” as a hallmark of cancer (Hanahan and Weinberg, 2000) needs to be revisited.\ud \ud Kim et al. (2011) begin by reviewing the interactions between a tumour and its microenvironment, highlighting how this plays an important role in the transition from benign or pre-malignant tumour to invasive cancer. They then describe a continuum model for the mechanics of a growing tumour in three spatial dimensions, and use it to investigate the effects on tumour growth of agarose gel inhomogeneities and other microenvironmental factors. This framework is extended to explore ductal carcinoma in situ (DCIS) in which the stroma is modelled as a continuum but the cells of the tumour are modelled discretely. The mechanical model is coupled to the biochemistry via a system of reaction–diffusion equations which describe the dynamics of key signalling factors. This multiscale model is solved numerically and effects of perturbing the system mechanically or biochemically are illustrated. This approach allows us to begin to understand the outcome of the nonlinear interactions of some of the fundamental processes involved in tumour growth, with the potential to then consider methods to control growth and spread.\ud \ud Gerlee and Anderson (2011) focus on mechanisms present in organisms that allow it, or parts of it, to maintain a given shape or architecture (structural homeostasis). They consider a hybrid CA model for a two-dimensional mono-layer of cells which may, for example, approximate the epithelial lining of an organ. In their model, each cell has an intracellular network which integrates the cues a cell receives from its microenvironment (for example nutrients or growth factors, whose dynamics are modelled by reaction-diffusion equations) and other cells and determines the response of the cell, in terms of its behaviour or phenotype. The problem is then reduced to finding a set of network parameters (or genotype) which maximises a fitness function such that structural homeostatis is attained. Perturbations of the system, such as wounding or mutation, are investigated.\ud \ud Vera et al. (2011) present an in-depth review which focuses on JAK-STAT (Janus kinase – signal transducer and activator of transcription) pathway in the context of cancer. This pathway plays a fundamental role in growth control, cell differentiation and maintenance of tissue homeostasis, and its dysregulation plays an important role in tumourigenesis. They review the biology of the pathway and then survey systems biology approaches that have helped elucidate the dynamics of the pathway under physiological and diseased states.\ud \ud Scianna et al., (2011) address the multiple levels of organisation involved in vascularisation, an important step enabling tumour growth and the formation of metastases. Their work forms an innovative multiscale hybrid framework within which to test potential anti-angiogenic strategies in treating cancer.\ud \ud Insuk Lee (2011) presents a holistic model of genes as a collaborative society. To the standard approaches involving protein–protein interaction networks (PPIN) and transcriptional regulatory networks (TRN) he adds the probabilistic functional gene network (PFGN) to show how robustness can arise despite noisy genomics data. Mapping epistatic interactions between genes is identified as the key way to understanding the genetic organisation of complex traits. Amongst the applications of this approach he considers epistatic interactions between hub cancer genes such as p53.\ud \ud Keith Baverstock (2011) uses models of cell regulation to address the important question of whether regulatory networks are hard wired into the genome or whether they are better represented as open systems involving an attractor interacting with the environment. In the latter case, environmental stress can trigger inherited transitions in the phenotype without necessarily involving DNA sequence changes. The second type of model works best. As he says “the power of the model lies in its ability to make evident how it is that a rigid and highly conserved coding sequence in DNA, the genotype, can give rise to phenotypic plasticity and responsiveness to environment” and that it helps to understand “the origins of non-genetic somatic and inherited disease, arising from switches to variant attractors representing phenotypes with abnormal characteristics.” The relevance to diseases like cancer is obvious.\ud \ud Taken as a whole, this set of articles not only challenges some of the current paradigms, but also lays the groundwork for alternative approaches and in many cases takes those approaches further towards the goal of understanding cancer as a systems-level process

Nonextensive triangle equality and other properties of Tsallis relative-entropy minimization

Kullback-Leibler relative-entropy has unique properties in cases involving distributions resulting from relative-entropy minimization. Tsallis relative-entropy is a one parameter generalization of Kullback-Leibler relative-entropy in the nonextensive thermostatistics. In this paper, we present the properties of Tsallis relative-entropy minimization and present some differences with the classical case. In the representation of such a minimum relative-entropy distribution, we highlight the use of the q-product, an operator that has been recently introduced to derive the mathematical structure behind the Tsallis statistics. One of our main results is generalization of triangle equality of relative-entropy minimization to the nonextensive case.Comment: 15 pages, change of title, revision of triangle equalit