Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology

The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/endoplasmic Ca(2 +) ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications.

Texture, realism, performance: exploring the intersection of transtexts and the contemporary sitcom

Contemporary US sitcom is at an interesting crossroads: it has received an increasing amount of scholarly attention (e.g. Mills 2009; Butler 2010; Newman and Levine 2012; Vermeulen and Whitfield 2013), which largely understands it as shifting towards the aesthetically and narratively complex. At the same time, in the post-broadcasting era, US networks are particularly struggling for their audience share. With the days of blockbuster successes like Must See TV’s Friends (NBC 1994-2004) a distant dream, recent US sitcoms are instead turning towards smaller, engaged audiences. Here, a cult sensibility of intertextual in-jokes, temporal and narrational experimentation (e.g. flashbacks and alternate realities) and self-reflexive performance styles have marked shows including Community (NBC 2009-2015), How I Met Your Mother (CBS 2005-2014), New Girl (Fox 2011-present) and 30 Rock (NBC 2006-2013). However, not much critical attention has so far been paid to how these developments in textual sensibility in contemporary US sitcom may be influenced by, and influencing, the use of transmedia storytelling practices, an increasingly significant industrial concern and rising scholarly field of enquiry (e.g. Jenkins 2006; Mittell 2015; Richards 2010; Scott 2010; Jenkins, Ford and Green 2013). This chapter investigates this mutual influence between sitcom and transmedia by taking as its case studies two network shows that encourage invested viewership through their use of transtexts, namely How I Met Your Mother (hereafter HIMHM) and New Girl (hereafter NG). As such, it will pay particular attention to the most transtextually visible character/actor from each show: HIMYM’s Barney Stinson, played by Neil Patrick Harris, and NG’s Schmidt, played by Max Greenfield. This chapter argues that these sitcoms do not simply have their particular textual sensibility and also (happen to) engage with transmedia practices, but that the two are mutually informing and defining. This chapter explores the relationships and interplay between sitcom aesthetics, narratives and transmedia storytelling (or industrial transtexts), focusing on the use of multiple delivery channels in order to disperse “integral elements of a fiction” (Jenkins, 2006 95-6), by official entities such as the broadcasting channels. The chapter pays due attention to the specific production contexts of both shows and how these inform their approaches to transtexts. This chapter’s conceptual framework will be particularly concerned with how issues of texture, the reality envelope and accepted imaginative realism, as well as performance and the actor’s input inform and illuminate contemporary sitcoms and transtexts, and will be the first scholarly research to do so. It will seek out points of connections between two (thus far) separate strands of scholarship and will move discussions on transtexts beyond the usual genre studied (i.e. science-fiction and fantasy), as well as make a contribution to the growing scholarship on contemporary sitcom by approaching it from a new critical angle. On the basis that transmedia scholarship stands to benefit from widening its customary genre choice (i.e. telefantasy) for its case studies and from making more use of in-depth close analysis in its engagement with transtexts, the chapter argues that notions of texture, accepted imaginative realism and the reality envelope, as well as performance and the actor’s input deserve to be paid more attention to within transtext-related scholarship.

The impact of two coupled cirrus microphysics-radiation parameterizations on the temperature and specific humidity biases in the tropical tropopause layer in a climate model

The impact of two different coupled cirrus microphysics-radiation parameterizations on the zonally averaged temperature and humidity biases in the tropical tropopause layer (TTL) of a Met Office climate model configuration is assessed. One parameterization is based on a linear coupling between a model prognostic variable, the ice mass mixing ratio, qi, and the integral optical properties. The second is based on the integral optical properties being parameterized as functions of qi and temperature, Tc, where the mass coefficients (i.e. scattering and extinction) are parameterized as nonlinear functions of the ratio between qi and Tc. The cirrus microphysics parameterization is based on a moment estimation parameterization of the particle size distribution (PSD), which relates the mass moment (i.e. second moment if mass is proportional to size raised to the power of 2 ) of the PSD to all other PSD moments through the magnitude of the second moment and Tc. This same microphysics PSD parameterization is applied to calculate the integral optical properties used in both radiation parameterizations and, thus, ensures PSD and mass consistency between the cirrus microphysics and radiation schemes. In this paper, the temperature-non-dependent and temperature-dependent parameterizations are shown to increase and decrease the zonally averaged temperature biases in the TTL by about 1 K, respectively. The temperature-dependent radiation parameterization is further demonstrated to have a positive impact on the specific humidity biases in the TTL, as well as decreasing the shortwave and longwave biases in the cloudy radiative effect. The temperature-dependent radiation parameterization is shown to be more consistent with TTL and global radiation observations.

Towards the main sequence: detailed analysis of weak line and post-T Tauri stars

A detailed study was performed for a sample of low-mass pre-main-sequence (PMS) stars, previously identified as weak-line T Tauri stars, which are compared to members of the Tucanae and Horologium Associations. Aiming to verify if there is any pattern of abundances when comparing the young stars at different phases, we selected objects in the range from 1 to 100 Myr, which covers most of PMS evolution. High-resolution optical spectra were acquired at European Southern Observatory and Observatorio do Pico dos Dias. The stellar fundamental parameters effective temperature and gravity were calculated by excitation and ionization equilibria of iron absorption lines. Chemical abundances were obtained via equivalent width calculations and spectral synthesis for 44 per cent of the sample, which shows metallicities within 0.5 dex solar. A classification was developed based on equivalent width of Li I 6708 angstrom and Ha lines and spectral types of the studied stars. This classification allowed a separation of the sample into categories that correspond to different evolutive stages in the PMS. The position of these stars in the Hertzsprung-Russell diagram was also inspected in order to estimate their ages and masses. Among the studied objects, it was verified that our sample actually contains seven weak-line T Tauri stars, three are Classical T Tauri, 12 are Fe/Ge PMS stars and 21 are post-T Tauri or young main-sequence stars. An estimation of circumstellar luminosity was obtained using a disc model to reproduce the observed spectral energy distribution. Most of the stars show low levels of circumstellar emission, corresponding to less than 30 per cent of the total emission.

COMPARISONS OF THE INTERSTELLAR MAGNETIC FIELD DIRECTIONS OBTAINED FROM THE IBEX RIBBON AND INTERSTELLAR POLARIZATIONS

Variations in the spatial configuration of the interstellar magnetic field (ISMF) near the Sun can be constrained by comparing the ISMF direction at the heliosphere found from the Interstellar Boundary Explorer (IBEX) spacecraft observations of a ""Ribbon"" of energetic neutral atoms (ENAs), with the ISMF direction derived from optical polarization data for stars within similar to 40 pc. Using interstellar polarization observations toward similar to 30 nearby stars within similar to 90 degrees of the heliosphere nose, we find that the best fits to the polarization position angles are obtained for a magnetic pole directed toward ecliptic coordinates of lambda, beta similar to 263 degrees, 37 degrees (or galactic coordinates of l, b similar to 38 degrees, 23 degrees), with uncertainties of +/- 35 degrees based on the broad minimum of the best fits and the range of data quality. This magnetic pole is 33 degrees from the magnetic pole that is defined by the center of the arc of the ENA Ribbon. The IBEX ENA ribbon is seen in sight lines that are perpendicular to the ISMF as it drapes over the heliosphere. The similarity of the polarization and Ribbon directions for the local ISMF suggests that the local field is coherent over scale sizes of tens of parsecs. The ISMF vector direction is nearly perpendicular to the flow of local interstellar material (ISM) through the local standard of rest, supporting a possible local ISM origin related to an evolved expanding magnetized shell. The local ISMF direction is found to have a curious geometry with respect to the cosmic microwave background dipole moment.

Interactive Vector Field Feature Identification

We introduce a flexible technique for interactive exploration of vector field data through classification derived from user-specified feature templates. Our method is founded on the observation that, while similar features within the vector field may be spatially disparate, they share similar neighborhood characteristics. Users generate feature-based visualizations by interactively highlighting well-accepted and domain specific representative feature points. Feature exploration begins with the computation of attributes that describe the neighborhood of each sample within the input vector field. Compilation of these attributes forms a representation of the vector field samples in the attribute space. We project the attribute points onto the canonical 2D plane to enable interactive exploration of the vector field using a painting interface. The projection encodes the similarities between vector field points within the distances computed between their associated attribute points. The proposed method is performed at interactive rates for enhanced user experience and is completely flexible as showcased by the simultaneous identification of diverse feature types.

Associating biosensing properties with the morphological structure of multilayers containing carbon nanotubes on field-effect devices

The control of molecular architecture provided by the layer-by-layer (LbL) technique has led to enhanced biosensors, in which advantageous features of distinct materials can be combined. Full optimization of biosensing performance, however, is only reached if the film morphology is suitable for the principle of detection of a specific biosensor. In this paper, we report a detailed morphology analysis of LbL films made with alternating layers of single-walled carbon nanotubes (SWNTs) and polyamidoamine (PAMAM) dendrimers, which were then covered with a layer of penicillinase (PEN). An optimized performance to detect penicillin G was obtained with 6-bilayer SWNT/PAMAM LbL films deposited on p-Si-SiO(2)-Ta(2)O(5) chips, used in biosensors based on a capacitive electrolyte-insulator-semiconductor (EIS) and a light-addressable potentiometric sensor (LAPS) structure, respectively. Field-emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) images indicated that the LbL films were porous, with a large surface area due to interconnection of SWNT into PAMAM layers. This morphology was instrumental for the adsorption of a larger quantity of PEN, with the resulting LbL film being highly stable. The experiments to detect penicillin were performed with constant-capacitance (Con Cap) and constant-current (CC) measurements for EIS and LAPS sensors, respectively, which revealed an enhanced detection signal and sensitivity of ca. 100 mV/decade for the field-effect sensors modified with the PAMAM/SWNT LbL film. It is concluded that controlling film morphology is essential for an enhanced performance of biosensors, not only in terms of sensitivity but also stability and response time. (C) 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Two-dimensional electron states bound to an off-plane donor in a magnetic field

The states of an electron confined in a two-dimensional (2D) plane and bound to an off-plane donor impurity center, in the presence of a magnetic field, are investigated. The energy levels of the ground state and the first three excited states are calculated variationally. The binding energy and the mean orbital radius of these states are obtained as a function of the donor center position and the magnetic field strength. The limiting cases are discussed for an in-plane donor impurity (i.e. a 2D hydrogen atom) as well as for the donor center far away from the 2D plane in strong magnetic fields, which corresponds to a 2D harmonic oscillator.

Action of the gravitational field on the dynamical Casimir effect

In this paper, we analyze the action of the gravitational field on the dynamical Casimir effect. We consider a massless scalar field confined in a cuboid cavity placed in a gravitational field described by a static and diagonal metric. With one of the plane mirrors of the cavity allowed to move, we compute the average number of particles created inside the cavity by means of the Bogoliubov coefficients computed through perturbative expansions. We apply our result to the case of an oscillatory motion of the mirror, assuming a weak gravitational field described by the Schwarzschild metric. The regime of parametric amplification is analyzed in detail, demonstrating that our computed result for the mean number of particles created agrees with specific associated cases in the literature. Our results, obtained in the framework of the perturbation theory, are restricted, under resonant conditions, to a short-time limit.

Skolutveckling som diskursiv praktik : Några ideologiska implikationer

This study aims at highlighting the ideological implications of school development as a discursive practice. More comprehensively the aim is also contributing to rearrangements and shifts in perspective when school development is the matter. One of today´s most widespread and dominant discourses are said to be the one which concerns development, and according to many interpreters, development is one of the most prominent commandments in the modern as well as the post-modern narratives. School development as a concept has for the last 15 years established itself firmly in both Swedish school policy and in Swedish school research. It may sound obvious and commendable but also such axioms may be questioned.The design of the study lies in the field of discourse research and more specifically within critical discursive psychology, which draws on both a post-structural and a postmodern conception of discourse. The study is based on the idea that the ideological potential of arguments occurs, develops and changes in discursive practices and not anywhere else or at any abstract level. The starting point is a perception that certain issues and topics within e.g. conversation, depending on time and context will be seen as controversial, while others will be taken for granted.One part of the basis of the study consists of texts with a direct bearing on a specific school research and development project which took place between 2003 and 2008. Participating partners in the collaboration were the Swedish National Agency for School Improvement, Karlstad University, Dalarna University and 13 municipalities in Sweden. Another part of the basis of the study consists of texts in which ‘school development’ is considered and negotiated in more general terms, usually without reference to the project. All texts derive from the period 2003 – 2006.The analysis shows that school development as discursive practice often rely on a set of stereotypical expressions and ways of arguing. Stereotypes, which among other things, tend to divide people into suitable and non-suitable, capable and non-capable, which may be regarded as a somewhat unexpected implication of school development. The material has been dramatized by an intrigue inspired by the sociologist Zygmunt Bauman´s texts. He has written extensively on the modern in relation to the postmodern and about the ambivalence which resides in between and school development as discursive practice can be understood in much the similar way.

Historielärares ämnesförståelse : Centrala begrepp i historielärares förståelse av skolämnet historia

This thesis focuses on four different aspects of history teachers’ comprehensiveunderstanding of the school subject history. More specifically, the aim is tostudy the comprehension of the subject as perceived by individual historyteachers. Special emphasis is placed on identifying the concepts of the field ofhistory that are central to the teachers’ understanding of the school subject history.The first aspect studied is the teachers’ biographical changes. In a life historyperspective it seems as if the teachers’ subject conception changes from anunproblematic and tentative approach to a more complex and confident understandingof the subject. The second aspect treated is the rationale behind theirgrasp of the purpose and content of the subject. Three major positions areidentified, namely educational (bildung) orientation, critical orientation, andidentity orientation.The third aspect studied is the teachers’ interpretation of a curriculumnew to them. The teachers placed the curriculum in the field of tension betweenan education policy position, emphasizing more precise knowledge, onthe one hand, and a history science position, emphasizing concepts of historicalconsciousness. The fourth aspect studied is five different conceptual tools displayedin the teachers’ remarks on having completed the teaching of a newcourse. These are termed ‘history as narrative’, ‘history as time-space’, ‘historyas explanation’, ‘history as perspective taking’, and ‘history as skills’At the general level the study shows not only that subject conception is ofimportance to the teachers’ understanding of their obligation as teachers of historybut also how it is formed and constantly transformed by many differentfactors. In this process it is clear that the concepts used by the teachers, althoughvariously defined, can be seen as specific to the school subject historyand essential to the construction of history as a school subject.

Towards a post-patriarchal gender order : Confronting the universality and the particularity of violence against women

The issues of gender equality and women’s human rights have become major spheres of academic debate, policy and activism in virtually every corner of the globe. Violence against women, a relative latecomer to the international gender agenda, has provided a particularly critical entry point in challenging long standing gender ideologies and taboos as well as the gender biased mainstream human rights framework that kept, until recently, the gender specific abuses women experience outside of public scrutiny.

Kommunal marknadsföring- Competitive identity och institutionell problematik : En komparativ fallstudie om två svenska kommuner och deras marknadsföring

Historiskt sett finns det etablerade normer i samhället som säger att en kommun endast ska bedriva traditionell kommunal verksamhet som innefattar att tillgodose välfärden (vård, skola & omsorg). Dock så har globaliseringen och urbaniseringen skapat en konkurrens om invånare vilket har lett till att kommuner idag bedriver en allt mer utvecklad marknadsföring för att attrahera fler invånare. Den här fallstudien innehåller två objekt (kommuner). Vi vill undersöka den kommunala marknadsföringen genom att fokusera på begreppen competitive identity (CI) och institutionell problematik (IP). Begreppet CI innehåller en teoretisk genomgång av komponenter i kommunal marknadsföring och IP beskriver kommunernas komplexa situation med olika institutionella krav. Genom att analysera dessa begrepp mot praktiska fall kan vi bidra till ökad förståelse om kommunal marknadsföring som är vårt syfte. Vi presenterar även en egen modell i samband med begreppet CI som ger en nyanserad bild av ämnet. Studiens resultat identifierar att kommunerna har speciella målgrupper som likt ett företag varierar beroende på deras ställning på marknaden. Genom skapandet av en CI deklarerar kommunen en önskvärd image där företeelser som inte bidrar till den blir exkluderade. Det gestaltar sig på olika sätt vilket analyseras grundligt i studien. Samtidigt illustreras motsägelsen när respondenterna i fallen säger att det är medborgarna som håller uppe imagen. Studien visar att det inte finns en enhetlig bild hur man som kommun ska hantera den institutionella komplexitet som uppstår. Fallen presenterar två olika synsätt som de finner mer lämpligt.