Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration

Satellite cells represent the stem cell population of adult skeletal muscle. The molecular mechanisms that control the proliferation of satellite cells are not well understood. In this study, we show that in response to injury, myofibres activate Wnt ligand transcription and activate a reporter cell line that is sensitive to the canonical Wnt-signalling pathway. Activated satellite cells on isolated cultured myofibres show robust expression of activated-β-catenin (Act-β-Cat), a key downstream transcriptional coactivator of canonical Wnt signalling. We provide evidence that the Wnt family of secreted glycoproteins act on satellite cells in a ligand-specific manner. Overexpression of Wnt1, Wnt3a or Wnt5a protein causes a dramatic increase in satellite-cell proliferation. By contrast, exposure of satellite cells to Wnt4 or Wnt6 diminishes this process. Moreover, we show that the prolonged satellite-cell quiescence induced by inhibitory Wnt is reversible and exposing inhibited satellite cells to stimulatory Wnt signalling restores their proliferation rate. Stimulatory Wnt proteins induce premature satellite cell BrdU incorporation as well as nuclear translocation of Act-β-Cat. Finally, we provide evidence that the Act-β-Cat translocation observed in single fibres during in vitro culture also occurs in cases of acute and chronic skeletal muscle regeneration in rodents and humans. We propose that Wnt proteins may be key factors that regulate the rate of satellite-cell proliferation on adult muscle fibres during the wound-healing response.

The linguistic status of Isotype

It is ironic that Otto Neurath, one of those responsible for the ‘linguistic turn’ in philosophy of the twentieth century, should have been concerned during the last twenty years of his life with developing a ‘pictorial language’. By using simplified pictograms as components, the Wiener Methode der Bildstatistik (later called Isotype) bypassed verbal language to a great extent, creating the potential for universal understanding of biological, social and economic correlations. However, despite its consistency and rigour, Isotype was not a complete language, and Neurath knew that it never could be. This paper will examine the linguistic characteristics of Isotype and describe the deliberate resistance on the part of its creators to develop a full theory behind it.

Numerical Methods for Stiff Two-Point Boundary Value Problems

We consider the two-point boundary value problem for stiff systems of ordinary differential equations. For systems that can be transformed to essentially diagonally dominant form with appropriate smoothness conditions, a priori estimates are obtained. Problems with turning points can be treated with this theory, and we discuss this in detail. We give robust difference approximations and present error estimates for these schemes. In particular we give a detailed description of how to transform a general system to essentially diagonally dominant form and then stretch the independent variable so that the system will satisfy the correct smoothness conditions. Numerical examples are presented for both linear and nonlinear problems.

TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration

Limb girdle muscular dystrophy type 2H (LGMD2H) is an inherited autosomal recessive disease of skeletal muscle caused by a mutation in the TRIM32 gene. Currently its pathogenesis is entirely unclear. Typically the regeneration process of adult skeletal muscle during growth or following injury is controlled by a tissue specific stem cell population termed satellite cells. Given that TRIM32 regulates the fate of mammalian neural progenitor cells through controlling their differentiation, we asked whether TRIM32 could also be essential for the regulation of myogenic stem cells. Here we demonstrate for the first time that TRIM32 is expressed in the skeletal muscle stem cell lineage of adult mice, and that in the absence of TRIM32, myogenic differentiation is disrupted. Moreover, we show that the ubiquitin ligase TRIM32 controls this process through the regulation of c-Myc, a similar mechanism to that previously observed in neural progenitors. Importantly we show that loss of TRIM32 function induces a LGMD2H-like phenotype and strongly affects muscle regeneration in vivo. Our studies implicate that the loss of TRIM32 results in dysfunctional muscle stem cells which could contribute to the development of LGMD2H.

Food restriction reverses the hyper-muscular phenotype and force generation capacity deficit of the myostatin null mouse

Food restriction has a great impact on skeletal muscle mass by inducing muscle protein breakdown to provide substrates for energy production through gluconeogenesis. Genetic models of hyper-muscularity interfere with the normal balance between protein synthesis and breakdown which eventually results in extreme muscle growth. Mutations or deletions in the myostatin gene result in extreme muscle mass. Here we evaluated the impact of food restriction for a period of 5 weeks on skeletal muscle size (i.e., fibre cross-sectional area), fibre type composition and contractile properties (i.e., tetanic and specific force) in myostatin null mice. We found that this hyper-muscular model was more susceptible to catabolic processes than wild type mice. The mechanism of skeletal muscle mass loss was examined and our data shows that the myostatin null mice placed on a low calorie diet maintained the activity of molecules involved in protein synthesis and did not up-regulate the expression of genes pivotal in ubiquitin-mediated protein degradation. However, we did find an increase in the expression of genes associated with autophagy. Surprisingly, the reduction on muscle size was followed by improved tetanic and specific force in the null mice compared to wild type mice. These data provide evidence that food restriction may revert the hyper-muscular phenotype of the myostatin null mouse restoring muscle function.

Interactions between shallow and deep convection under a finite departure from convective quasi–equilibrium

The present paper presents a simple theory for the transformation of non-precipitating, shallow convection into precipitating, deep convective clouds. In order to make the pertinent point a much idealized system is considered, consisting only of shallow and deep convection without large–scale forcing. The transformation is described by an explicit coupling between these two types of convection. Shallow convection moistens and cools the atmosphere, whereas deep convection dries and warms, leading to destabilization and stabilization respectively. Consequently, in their own stand–alone modes, shallow convection perpetually grows, whereas deep convection simply damps: the former never reaches equilibrium, and the latter is never spontaneously generated. Coupling the modes together is the only way to reconcile these undesirable separate tendencies so that the convective system as a whole can remain in a stable periodic state under this idealized setting. Such coupling is a key missing element in current global atmospheric models. The energy–cycle description as originally formulated by Arakawa and Schubert, and presented herein is suitable for direct implementation into models using a mass–flux parameterization, and would alleviate the current problems with the representation of these two types of convection in numerical models. The present theory also provides a pertinent framework for analyzing large–eddy simulations and cloud–resolving modelling.

Convective quasi–equilibrium

The concept of convective quasi–equilibrium (CQE) is a key ingredient in order to understand the role of deep moist convection in the atmosphere. It has been used as a guiding principle to develop almost all convective parameterizations and provides a basic theoretical framework for large–scale tropical dynamics. The CQE concept as originally proposed by Arakawa and Schubert [1974] is systematically reviewed from wider perspectives. Various interpretations and extensions of Arakawa and Schubert’s CQE are considered in terms of both a thermodynamic analogy and as a dynamical balance. The thermodynamic interpretations can be more emphatically embraced as a homeostasis. The dynamic balance interpretations can be best understood by analogy with the slow manifold. Various criticisms of CQE can be avoided by taking the dynamic balance interpretation. Possible limits of CQE are also discussed, including the importance of triggering in many convective situations, as well as the possible self–organized criticality of tropical convection. However, the most intriguing aspect of the CQE concept is that, in spite of many observational tests supporting and interpreting it in many different senses, it has 1never been established in a robust manner based on a systematic analysis of the cloud–work function budget by observations as was originally defined.

Adeno-associated virus-8-Mediated intravenous transfer of myostatin propeptide leads to systemic functional improvements of slow but not fast muscle

Myostatin is a member of the transformating growth factor-_ (TGF-_) superfamily of proteins and is produced almost exclusively in skeletal muscle tissue, where it is secreted and circulates as a serum protein. Myostatin acts as a negative regulator of muscle mass through the canonical SMAD2/3/4 signaling pathway. Naturally occurring myostatin mutants exhibit a ‘double muscling’ phenotype in which muscle mass is dramatically increased as a result of both hypertrophy and hyperplasia. Myostatin is naturally inhibited by its own propeptide; therefore, we assessed the impact of adeno associated virus-8 (AAV8) myostatin propeptide vectors when systemically introduced in MF-1 mice. We noted a significant systemic increase in muscle mass in both slow and fast muscle phenotypes, with no evidence of hyperplasia; however, the nuclei-to- cytoplasm ratio in all myofiber types was significantly reduced. An increase in muscle mass in slow (soleus) muscle led to an increase in force output; however, an increase in fast (extensor digitorum longus [EDL]) muscle mass did not increase force output. These results suggest that the use of gene therapeutic regimens of myostatin inhibition for age-related or disease-related muscle loss may have muscle-specific effects.

Addressee orientation in political speeches: tracing the dialogical 'other' in argumentative monologue

This article suggests that the addressees as the dialogical ‘other’ loom large in monological political speeches. However, political speeches are produced under conditions of addressee heterogeneity, i.e. the speakers do not actually know who they will be talking to. It will be argued that the addressees are nevertheless a crucial element in speakers’ context models, that speakers orientate towards imagined addressees and that certain aspects – what possible addressees may do, think or believe and that they are a part of an imagined community – are particularly relevant from the speakers’ point of view. An analysis of addressee orientation in political speeches aims at reconstructing speakers’ conceptualisations of possible addressees. The analysis reveals patterns of addressee orientation which suggest that the addressees are framed in terms of presumed nearness (i.e. agreement) or distance (i.e. disagreement) to the speakers. Both presumed agreement and disagreement will be discussed in terms of how the speakers aim to impose their default perspectives on the addressees. The analysis is based on examples from a substantial corpus of German chancellors’ political speeches from 1951-2001.

Towards global drought early warning capability: expanding international cooperation for the development of a framework for global drought monitoring and forecasting

Drought is a global problem that has far-reaching impacts and especially 47 on vulnerable populations in developing regions. This paper highlights the need for a Global Drought Early Warning System (GDEWS), the elements that constitute its underlying framework (GDEWF) and the recent progress made towards its development. Many countries lack drought monitoring systems, as well as the capacity to respond via appropriate political, institutional and technological frameworks, and these have inhibited the development of integrated drought management plans or early warning systems. The GDEWS will provide a source of drought tools and products via the GDEWF for countries and regions to develop tailored drought early warning systems for their own users. A key goal of a GDEWS is to maximize the lead time for early warning, allowing drought managers and disaster coordinators more time to put mitigation measures in place to reduce the vulnerability to drought. To address this, the GDEWF will take both a top-down approach to provide global real-time drought monitoring and seasonal forecasting, and a bottom-up approach that builds upon existing national and regional systems to provide continental to global coverage. A number of challenges must be overcome, however, before a GDEWS can become a reality, including the lack of in-situ measurement networks and modest seasonal forecast skill in many regions, and the lack of infrastructure to translate data into useable information. A set of international partners, through a series of recent workshops and evolving collaborations, has made progress towards meeting these challenges and developing a global system.

Isotype in Africa, 1952–58

A review of work done by the Isotype Institute in the 1940s and 1950s, associated with Africa. The chapter discusses Otto Neurath's growing interest in the last years of his life in the issue of presenting information to (West) Africans through Isotype methods. Although this interest was not realised by Otto Neurath in the form of completed work during his lifetime, Marie Neurath and the Isotype Institute did successfully carry out numerous projects in Britain's West African colonies during the 1950s, in Sierra Leone, Gold Coast (Ghana), and most extensively in the Western Region of Nigeria. Discussion of these projects illustrates the means by which Isotype work was carried out in a developing world context, the difficulties that were encountered, and the issues of effectiveness and sustainability the work raised.

Interferometric technique for measuring terahertz antenna phase patterns

A quasi-optical interferometric technique capable of measuring antenna phase patterns without the need for a heterodyne receiver is presented. It is particularly suited to the characterization of terahertz antennas feeding power detectors or mixers employing quasi-optical local oscillator injection. Examples of recorded antenna phase patterns at frequencies of 1.4 and 2.5 THz using homodyne detectors are presented. To our knowledge, these are the highest frequency antenna phase patterns ever recovered. Knowledge of both the amplitude and phase patterns in the far field enable a Gauss-Hermite or Gauss-Laguerre beam-mode analysis to be carried out for the antenna, of importance in performance optimization calculations, such as antenna gain and beam efficiency parameters at the design and prototype stage of antenna development. A full description of the beam would also be required if the antenna is to be used to feed a quasi-optical system in the near-field to far-field transition region. This situation could often arise when the device is fitted directly at the back of telescopes in flying observatories. A further benefit of the proposed technique is simplicity for characterizing systems in situ, an advantage of considerable importance as in many situations, the components may not be removable for further characterization once assembled. The proposed methodology is generic and should be useful across the wider sensing community, e.g., in single detector acoustic imaging or in adaptive imaging array applications. Furthermore, it is applicable across other frequencies of the EM spectrum, provided adequate spatial and temporal phase stability of the source can be maintained throughout the measurement process. Phase information retrieval is also of importance to emergent research areas, such as band-gap structure characterization, meta-materials research, electromagnetic cloaking, slow light, super-lens design as well as near-field and virtual imaging applications.

Evaluation of climate models using palaeoclimatic data.

There is large uncertainty about the magnitude of warming and how rainfall patterns will change in response to any given scenario of future changes in atmospheric composition and land use. The models used for future climate projections were developed and calibrated using climate observations from the past 40 years. The geologic record of environmental responses to climate changes provides a unique opportunity to test model performance outside this limited climate range. Evaluation of model simulations against palaeodata shows that models reproduce the direction and large-scale patterns of past changes in climate, but tend to underestimate the magnitude of regional changes. As part of the effort to reduce model-related uncertainty and produce more reliable estimates of twenty-first century climate, the Palaeoclimate Modelling Intercomparison Project is systematically applying palaeoevaluation techniques to simulations of the past run with the models used to make future projections. This evaluation will provide assessments of model performance, including whether a model is sufficiently sensitive to changes in atmospheric composition, as well as providing estimates of the strength of biosphere and other feedbacks that could amplify the model response to these changes and modify the characteristics of climate variability.