Kinetic proofreading models for cell signaling predict ways to escape kinetic proofreading

In the context of cell signaling, kinetic proofreading was introduced to explain how cells can discriminate among ligands based on a kinetic parameter, the ligand-receptor dissociation rate constant. In the kinetic proofreading model of cell signaling, responses occur only when a bound receptor undergoes a complete series of modifications. If the ligand dissociates prematurely, the receptor returns to its basal state and signaling is frustrated. We extend the model to deal with systems where aggregation of receptors is essential to signal transduction, and present a version of the model for systems where signaling depends on an extrinsic kinase. We also investigate the kinetics of signaling molecules, “messengers,” that are generated by aggregated receptors but do not remain associated with the receptor complex. We show that the extended model predicts modes of signaling that exhibit kinetic discrimination for some range of parameters but for other parameter values show little or no discrimination and thus escape kinetic proofreading. We compare model predictions with experimental data.

The Limits of Marijuana Legalization in the States

Although some ingenious solutions have been proposed to the problems posed by Section 280E pf the federal tax code, the situation remains untenable. The only solution to this current conundrum is a change in federal law; so long as marijuana remains illegal under the Controlled Substances Act, state marijuana policy will inevitably be frustrated. This brief response to an article by Professor Leff identifies some of these frustrations and proposes a few modest federal solutions

Patients' and professionals' views on managing fibromyalgia

BACKGROUND: Managing fibromyalgia is a challenge for both health care systems and the professionals caring for these patients, due, in part, to the fact that the etiology of this disease is unknown, its symptoms are not specific and there is no standardized treatment. OBJECTIVE: The present study examines three aspects of fibromyalgia management, namely diagnostic approach, therapeutic management and the health professional-patient relationship, to explore specific areas of the health care process that professionals and patients may consider unsatisfactory. METHODS: A qualitative study involving semistructured interviews with 12 fibromyalgia patients and nine health professionals was performed. RESULTS: The most commonly recurring theme was the dissatisfaction of both patients and professionals with the management process as a whole. Both groups expressed dissatisfaction with the delay in reaching a diagnosis and obtaining effective treatment. Patients reported the need for greater moral support from professionals, whereas the latter often felt frustrated and of little help to patients. Patients and professionals agreed on one point: the uncertainty surrounding the management of fibromyalgia and, especially, its etiology. CONCLUSION: The present study contributes to a better understanding regarding why current management of fibromyalgia is neither effective nor satisfactory. It also provides insight into how health professionals can support fibromyalgia patients to achieve beneficial results. Health care services should offer greater support for these patients in the form of specific resources such as fibromyalgia clinics and health professionals with increased awareness of the disease.

spotlight europe #2013/04, May 2013: The Changing Face of North Africa. An Opportunity for and with Europe.

North Africa is changing fast, and its youthful societies look back with pride at their recent uprisings. However, they are also getting frustrated by the fact that the economic outlook is not improving. Europe’s role in the strategically important southern Mediterranean area needs to be realigned in order to promote the development of democracy, employment opportunities, and security. There is a great deal of potential for cooperation with Morocco, Algeria, Tunisia, Libya and Egypt.

spotlight Europe 2013/04 — Mai 2013: Nordafrika im Wandel – Chancen mit und für Europa = North Africa in change - an opportunity for and with Europe

North Africa’s youthful societies look back with pride at their recent uprisings. However, they are also getting frustrated by the fact that the economic outlook is not improving. Europe’s role in the southern Mediterranean area needs to be realigned in order to promote the development of democracy, employment opportunities, and security. Because "there is a great deal of potential for cooperation with Morocco, Algeria, Tunisia, Libya and Egypt?" argue our authors Christian P. Hanelt and Sven Behrendt.

Cittadinanza, lavoro e diritti sociali nella crisi europea = Citizenship, work and social rights in the European crisis. WP C.S.D.L.E. “Massimo D’Antona”.INT – 100/2013

This paper explores the limits and potentials of European citizenship as a transnational form of social integration, taking as comparison Marshall's classical analysis of the historical development of social rights in the context of the national Welfare State. It is submitted that this potential is currently frustrated by the prevailing negative-integration dimension in which the interplay between Union citizenship and national systems of Welfare State takes place. This negative dimension pervades the entire case law of the Court of Justice on Union citizenship, even becoming dominant – after the famous Viking and Laval judgements – in the ways in which the judges in Luxembourg have built, and limited, what in Marshall’s terms might be called the European collective dimension of “industrial citizenship”. The new architecture of the economic and monetary governance of the Union, based as it is on an unprecedented effort towards a creeping constitutionalisation of a neo-liberal politics of austerity and welfare retrenchment, is destined to strengthen the de-structuring pressures on the industrial-relation and social protection systems of the member States. The conclusions sum-up the main critical arguments and make some suggestions for an alternative path for re-politicising the social question in Europe.

Georgian drift. The crisis of Georgia's way westwards. OSW POINT OF VIEW 57, 2016-02-22

For several years Georgia has been experiencing processes which may be interpreted as symptoms of a deepening, multidimensional social and political crisis. Reforms have lost momentum, stagnation has set in, and in some areas the situation has begun to revert to the pre-revolution status (including rising crime levels). The Georgian political system has found itself in a serious crisis, while society has become increasingly frustrated and apathetic, mainly because people’s standards of living have been stagnating. This political and social malaise has been breeding Euro-scepticism and disenchantment with the West. A country that had been firmly navigating westwards, Georgia has now started drifting and slipping into malaise. This risks reversing what the country has achieved so far in the internal dimension, increasing instability and triggering a crisis in the pro-Western vector of Tbilisi’s foreign policy. While that may not necessarily mean a turn towards Russia, in the present situation it has been easier for Moscow to pursue its own interests in the region. Should Tbilisi’s pro-Western course become reversed or permanently stagnant, that would entail grave consequences for the country itself and beyond. It would be a defeat for the West and would undermine the European aspirations of countries like Ukraine or Moldova.

Older people with hearing impairment: A literature review of the spouse's perspective

Spouses of older people with hearing impairment frequently urge their hearing impaired partners to seek help for their hearing difficulties. Only a minority of individuals with hearing impairment are self-motivated, with the majority of clients, especially older clients, presenting at audiology clinics under the persuasion or influence of their spouse or significant other. This highlights the important role that spouses play in initiating aural rehabilitation and indicates that spouses of older people with hearing impairment may become so frustrated with their partners' hearing loss that they are often the primary reason why the hearing impaired person presents for audiological services. To date, however, the number of studies addressing the effect of hearing loss on significant others is limited. Those studies that have investigated the effect of hearing impairment on families are commonly focused on the person with the impairment and most commonly, the significant other has merely been used as a proxy to describe the perceived problems of his or her spouse. Further, there has been no systematic indepth investigation of the needs of spouses of older people with hearing impairment, including the effect of retirement and the increase in time spent together, with the majority of studies focusing primarily on younger spouses of workers affected by noise-induced hearing loss. The cumulative effect of experiencing many years of hearing difficulties with a partner may also influence the extent to which older spouses are affected by hearing impairment. The primary purpose of this article is therefore to critically review the existing literature on the effects of hearing impairment on spouses. It will also provide a rationale for the importance of this topic as a clinical issue and suggest some future directions for research in this area.

Energy as an entanglement witness for quantum many-body systems

We investigate quantum many-body systems where all low-energy states are entangled. As a tool for quantifying such systems, we introduce the concept of the entanglement gap, which is the difference in energy between the ground-state energy and the minimum energy that a separable (unentangled) state may attain. If the energy of the system lies within the entanglement gap, the state of the system is guaranteed to be entangled. We find Hamiltonians that have the largest possible entanglement gap; for a system consisting of two interacting spin-1/2 subsystems, the Heisenberg antiferromagnet is one such example. We also introduce a related concept, the entanglement-gap temperature: the temperature below which the thermal state is certainly entangled, as witnessed by its energy. We give an example of a bipartite Hamiltonian with an arbitrarily high entanglement-gap temperature for fixed total energy range. For bipartite spin lattices we prove a theorem demonstrating that the entanglement gap necessarily decreases as the coordination number is increased. We investigate frustrated lattices and quantum phase transitions as physical phenomena that affect the entanglement gap.

Mixed order parameters, accidental nodes and broken time reversal symmetry in organic superconductors: a group theoretical analysis

We present a group theoretical analysis of several classes of organic superconductor. We predict that highly frustrated organic superconductors, such as K-(ET)(2)Cu-2(CN)(3) (where ET is BEDT-TTF, bis(ethylenedithio) tetrathiafulvalene) and beta'-[Pd(dmit)(2)](2)X, undergo two superconducting phase transitions, the first from the normal state to a d-wave superconductor and the second to a d + id state. We show that the monoclinic distortion of K-(ET)(2)Cu(NCS)(2) means that the symmetry of its superconducting order parameter is different from that of orthorhombic-K-(ET)(2)Cu[N(CN)(2)] Br. We propose that beta'' and theta phase organic superconductors have d(xy) + s order parameters.

Strong electronic correlations in superconducting organic charge transfer salts

We review the role of strong electronic correlations in quasi-two-dimensional organic charge transfer salts such as (BEDT-TTF)(2)X, (BETS)(2)Y, and beta'-[Pd(dmit)(2)](2)Z. We begin by defining minimal models for these materials. It is necessary to identify two classes of material: the first class is strongly dimerized and is described by a half-filled Hubbard model; the second class is not strongly dimerized and is described by a quarter-filled extended Hubbard model. We argue that these models capture the essential physics of these materials. We explore the phase diagram of the half-filled quasi-two-dimensional organic charge transfer salts, focusing on the metallic and superconducting phases. We review work showing that the metallic phase, which has both Fermi liquid and 'bad metal' regimes, is described both quantitatively and qualitatively by dynamical mean field theory (DMFT). The phenomenology of the superconducting state is still a matter of contention. We critically review the experimental situation, focusing on the key experimental results that may distinguish between rival theories of superconductivity, particularly probes of the pairing symmetry and measurements of the superfluid stiffness. We then discuss some strongly correlated theories of superconductivity, in particular the resonating valence bond (RVB) theory of superconductivity. We conclude by discussing some of the major challenges currently facing the field. These include parameterizing minimal models, the evidence for a pseudogap from nuclear magnetic resonance (NMR) experiments, superconductors with low critical temperatures and extremely small superfluid stiffnesses, the possible spin- liquid states in kappa-(ET)(2)Cu-2(CN)(3) and beta'-[Pd(dmit)(2)](2)Z, and the need for high quality large single crystals.

Excitation spectra of the spin-1/2 triangular-lattice Heisenberg antiferromagnet

We use series expansion methods to calculate the dispersion relation of the one-magnon excitations for the spin-(1)/(2) triangular-lattice nearest-neighbor Heisenberg antiferromagnet above a three-sublattice ordered ground state. Several striking features are observed compared to the classical (large-S) spin-wave spectra. Whereas, at low energies the dispersion is only weakly renormalized by quantum fluctuations, significant anomalies are observed at high energies. In particular, we find rotonlike minima at special wave vectors and strong downward renormalization in large parts of the Brillouin zone, leading to very flat or dispersionless modes. We present detailed comparison of our calculated excitation energies in the Brillouin zone with the spin-wave dispersion to order 1/S calculated recently by Starykh, Chubukov, and Abanov [Phys. Rev. B74, 180403(R) (2006)]. We find many common features but also some quantitative and qualitative differences. We show that at temperatures as low as 0.1J the thermally excited rotons make a significant contribution to the entropy. Consequently, unlike for the square lattice model, a nonlinear sigma model description of the finite-temperature properties is only applicable at temperatures < 0.1J. Finally, we review recent NMR measurements on the organic compound kappa-(BEDT-TTF)(2)Cu-2(CN)(3). We argue that these are inconsistent with long-range order and a description of the low-energy excitations in terms of interacting magnons, and that therefore a Heisenberg model with only nearest-neighbor exchange does not offer an adequate description of this material.

Determinants of biological activity of nanomaterials in innate immunity cells: the role of aspect ratio, environmental contaminants and protein corona

As defined by the European Union, “ ’Nanomaterial’ (NM) means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or agglomerate, where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm-100 nm ” (2011/696/UE). Given their peculiar physico-chemical features, nanostructured materials are largely used in many industrial fields (e.g. cosmetics, electronics, agriculture, biomedical) and their applications have astonishingly increased in the last fifteen years. Nanostructured materials are endowed with very large specific surface area that, besides making them very useful in many industrial processes, renders them very reactive towards the biological systems and, hence, potentially endowed with significant hazard for human health. For these reasons, in recent years, many studies have been focused on the identification of toxic properties of nanostructured materials, investigating, in particular, the mechanisms behind their toxic effects as well as their determinants of toxicity. This thesis investigates two types of nanostructured TiO2 materials, TiO2 nanoparticles (NP), which are yearly produced in tonnage quantities, and TiO2 nanofibres (NF), a relatively novel nanomaterial. Moreover, several preparations of MultiWalled Carbon Nanotubes (MWCNT), another nanomaterial widely present in many products, are also investigated.- Although many in vitro and in vivo studies have characterized the toxic properties of these materials, the identification of their determinants of toxicity is still incomplete. The aim of this thesis is to identify the structural determinants of toxicity, using several in vitro models. Specific fields of investigation have been a) the role of shape and the aspect ratio in the determination of biological effects of TiO2 nanofibres of different length; b) the synergistic effect of LPS and TiO2 NP on the expression of inflammatory markers and the role played therein by TLR-4; c) the role of functionalization and agglomeration in the biological effects of MWCNT. As far as biological effects elicited by TiO2 NF are concerned, the first part of the thesis demonstrates that long TiO2 nanofibres caused frustrated phagocytosis, cytotoxicity, hemolysis, oxidative stress and epithelial barrier perturbation. All these effects were mitigated by fibre shortening through ball-milling. However, short TiO2 NF exhibited enhanced ability to activate acute pro-inflammatory effects in macrophages, an effect dependent on phagocytosis. Therefore, aspect ratio reduction mitigated toxic effects, while enhanced macrophage activation, likely rendering the NF more prone to phagocytosis. These results suggest that, under in vivo conditions, short NF will be associated with acute inflammatory reaction, but will undergo a relatively rapid clearance, while long NF, although associated with a relatively smaller acute activation of innate immunity cells, are not expected to be removed efficiently and, therefore, may be associated to chronic inflammatory responses. As far as the relationship between the effects of TiO2 NP and LPS, investigated in the second part of the thesis, are concerned, TiO2 NP markedly enhanced macrophage activation by LPS through a TLR-4-dependent intracellular pathway. The adsorption of LPS onto the surface of TiO2 NP led to the formation of a specific bio-corona, suggesting that, when bound to TiO2 NP, LPS exerts a much more powerful pro-inflammatory effect. These data suggest that the inflammatory changes observed upon exposure to TiO2 NP may be due, at least in part, to their capability to bind LPS and, possibly, other TLR agonists, thus enhancing their biological activities. Finally, the last part of the thesis demonstrates that surface functionalization of MWCNT with amino or carboxylic groups mitigates the toxic effects of MWCNT in terms of macrophage activation and capability to perturb epithelial barriers. Interestingly, surface chemistry (in particular surface charge) influenced the protein adsorption onto the MWCNT surface, allowing to the formation of different protein coronae and the tendency to form agglomerates of different size. In particular functionalization a) changed the amount and the type of proteins adsorbed to MWCNT and b) enhanced the tendency of MWCNT to form large agglomerates. These data suggest that the different biological behavior of functionalized and pristine MWCNT may be due, at least in part, to the different tendency to form large agglomerates, which is significantly influenced by their different capability to interact with proteins contained in biological fluids. All together, these data demonstrate that the interaction between physico-chemical properties of nanostructured materials and the environment (cells + biological fluids) in which these materials are present is of pivotal importance for the understanding of the biological effects of NM. In particular, bio-persistence and the capability to elicit an effective inflammatory response are attributable to the interaction between NM and macrophages. However, the interaction NM-cells is heavily influenced by the formation at the nano-bio interface of specific bio-coronae that confer a novel biological identity to the nanostructured materials, setting the basis for their specific biological activities.

Magnetic properties and Spin dynamics in magnetic Molecular Rings

Molecular nanomagnets are spin clusters whose topology and magnetic interactions can be modulated at the level of the chemical synthesis. They are formed by a small number of transition metal ions coupled by the Heisenberg's exchange interactions. Each cluster is magnetically isolated from its neighbors by organic ligands, making each unit not interacting with the others. Therefore, we can investigate the magnetic properties of an isolated molecular nanomagnet by bulk measurements. The present thesis has been mostly devoted to the experimental investigation of the magnetic properties and spin dynamics of different classes of antiferromagnetic (AF) molecular rings. This study has been exploiting various techniques of investigations, such as Nuclear Magnetic Resonance (NMR), muon spin relaxation (muSR) and SQUiD magnetometry. We investigate the magnetic properties and the phonon-induced relaxation dynamics of the first regular Cr9 antiferromagnetic (AF) ring, which represents a prototype frustrated AF ring. The magnetically-open AF rings like Cr8Cd are model systems for the study of the microscopic magnetic behaviour of finite AF Heisenberg chains. In this type of system the different magnetic behaviour depends length and on the parity of the chain (odd or even). In order to study the local spin densities on the Cr sites, the Cr-NMR spectra was collected at low temperature. The experimental result confirm the theoretical predictions for the spin configuration. Finally, the study of Dy6, the first rare-earth based ring that has been ever synthesized, has been performed by AC-SQuID and muSR measurements. We found that the dynamics is characterized by more than one characteristic correlation time, whose values depend strongly on the applied field.

Ilusão e realidade em Ivaporunduva: a televisão na cultura quilombola. Análise a partir da Folkmídia

Este estudo de caso visa, a partir de pesquisa de campo, pesquisa bibliográfica e entrevistas abertas observar como a televisão, enquanto meio de comunicação de massa, transforma ou influencia a cultura de uma comunidade quilombola. O objeto desta análise é a comunidade quilombola de Ivaporunduva, na área rural da cidade de Eldorado Paulista, região do Vale do Ribeira, interior do estado de São Paulo. Seus modos de vida têm sido constantemente ameaçados pela intenção da construção de barragens na cabeceira do rio Ribeira de Iguape, na margem do qual localizam-se diversas comunidades quilombolas, inclusive Ivaporunduva; pela falta de políticas públicas que resguardem verdadeiramente seus direitos, e pela falta de trabalho, o que acarreta na saída dos jovens da comunidade em busca de novos horizontes. A televisão faz parte de um novo universo na realidade quilombola e entra na vida desses homens e mulheres do campo como veículo de entretenimento e porta para um mundo de ilusões e realidades onde buscam encontrar-se e muitas vezes se frustram. A cultura quilombola e suas transformações depois da entrada da televisão em Ivaporunduva serão analisadas a partir da Folkmídia, espaço teórico que analisa a maneira pela qual os meios de comunicação abstraem elementos da cultura popular e vice-versa. É o vice-versa que aqui nos importa.