Cellular and molecular investigations into the development of the pectoral girdle

The forelimbs of higher vertebrates are composed of two portions: the appendicular region (stylopod, zeugopod and autopod) and the less prominent proximal girdle elements (scapula and clavicle) that brace the limb to the main trunk axis. We show that the formation of the muscles of the proximal limb occurs through two distinct mechanisms. The more superficial girdle muscles (pectoral and latissimus dorsi) develop by the “In–Out” mechanism whereby migration of myogenic cells from the somites into the limb bud is followed by their extension from the proximal limb bud out onto the thorax. In contrast, the deeper girdle muscles (e.g. rhomboideus profundus and serratus anterior) are induced by the forelimb field which promotes myotomal extension directly from the somites. Tbx5 inactivation demonstrated its requirement for the development of all forelimb elements which include the skeletal elements, proximal and distal muscles as well as the sternum in mammals and the cleithrum of fish. Intriguingly, the formation of the diaphragm musculature is also dependent on the Tbx5 programme. These observations challenge our classical views of the boundary between limb and trunk tissues. We suggest that significant structures located in the body should be considered as components of the forelimb.

The occipital lateral plate mesoderm is a novel source for vertebrate neck musculature

In vertebrates, body musculature originates from somites, whereas head muscles originate from the cranial mesoderm. Neck muscles are located in the transition between these regions. We show that the chick occipital lateral plate mesoderm has myogenic capacity and gives rise to large muscles located in the neck and thorax. We present molecular and genetic evidence to show that these muscles not only have a unique origin, but additionally display a distinct temporal development, forming later than any other muscle group described to date. We further report that these muscles, found in the body of the animal, develop like head musculature rather than deploying the programme used by the trunk muscles. Using mouse genetics we reveal that these muscles are formed in trunk muscle mutants but are absent in head muscle mutants. In concordance with this conclusion, their connective tissue is neural crest in origin. Finally, we provide evidence that the mechanism by which these neck muscles develop is conserved in vertebrates.

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.

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.

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.

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.

Climatic impacts of fresh water hosing under Last Glacial Maximum conditions: a multi-model study

Fresh water hosing simulations, in which a fresh water flux is imposed in the North Atlantic to force fluctuations of the Atlantic Meridional Overturning Circulation, have been routinely performed, first to study the climatic signature of different states of this circulation, then, under present or future conditions, to investigate the potential impact of a partial melting of the Greenland ice sheet. The most compelling examples of climatic changes potentially related to AMOC abrupt variations, however, are found in high resolution palaeo-records from around the globe for the last glacial period. To study those more specifically, more and more fresh water hosing experiments have been performed under glacial conditions in the recent years. Here we compare an ensemble constituted by 11 such simulations run with 6 different climate models. All simulations follow a slightly different design, but are sufficiently close in their design to be compared. They all study the impact of a fresh water hosing imposed in the extra-tropical North Atlantic. Common features in the model responses to hosing are the cooling over the North Atlantic, extending along the sub-tropical gyre in the tropical North Atlantic, the southward shift of the Atlantic ITCZ and the weakening of the African and Indian monsoons. On the other hand, the expression of the bipolar see-saw, i.e., warming in the Southern Hemisphere, differs from model to model, with some restricting it to the South Atlantic and specific regions of the southern ocean while others simulate a widespread southern ocean warming. The relationships between the features common to most models, i.e., climate changes over the north and tropical Atlantic, African and Asian monsoon regions, are further quantified. These suggest a tight correlation between the temperature and precipitation changes over the extra-tropical North Atlantic, but different pathways for the teleconnections between the AMOC/North Atlantic region and the African and Indian monsoon regions.

Isotype: design and contexts 1925–1971

The work in graphic communication carried out by Otto Neurath and his associates – now commonly known simply as Isotype – has been the subject of much interest in recent years. Conceived and developed in the 1920s as ‘the Vienna method of pictorial statistics’, this approach to designing information had from its inception the power to grow and spread internationally. Political developments in Europe played their part in its development, and production moved to the Netherlands (1934) and to England (1940), where the Isotype Institute continued to produce work until 1971. Bringing together the latest research, this book is the first comprehensive, detailed account of its subject. The Austrian, Dutch, and English years of Isotype are described here freshly and extensively. There are chapters on the notable extensions of Isotype to Soviet Russia, the USA, and Africa. Isotype work in film and in designing for children is fully documented and discussed. Between these main chapters the book presents interludes documenting Isotype production visually. Three appendices reprint key documents. In its international coverage and its extensions into the wider terrain of history, this book opens a new vista in graphic design.

Evaluation of coupled ocean-atmosphere simulations of northern hemisphere extratropical climates in the mid-Holocene

We have used the BIOME4 biogeography–biochemistry model and comparison with palaeovegetation data to evaluate the response of six ocean–atmosphere general circulation models to mid-Holocene changes in orbital forcing in the mid- to high-latitudes of the northern hemisphere. All the models produce: (a) a northward shift of the northern limit of boreal forest, in response to simulated summer warming in high-latitudes. The northward shift is markedly asymmetric, with larger shifts in Eurasia than in North America; (b) an expansion of xerophytic vegetation in mid-continental North America and Eurasia, in response to increased temperatures during the growing season; (c) a northward expansion of temperate forests in eastern North America, in response to simulated winter warming. The northward shift of the northern limit of boreal forest and the northward expansion of temperate forests in North America are supported by palaeovegetation data. The expansion of xerophytic vegetation in mid-continental North America is consistent with palaeodata, although the extent may be over-estimated. The simulated expansion of xerophytic vegetation in Eurasia is not supported by the data. Analysis of an asynchronous coupling of one model to an equilibrium-vegetation model suggests vegetation feedback exacerbates this mid-continental drying and produces conditions more unlike the observations. Not all features of the simulations are robust: some models produce winter warming over Europe while others produce winter cooling. As a result, some models show a northward shift of temperate forests (consistent with, though less marked than, the expansion shown by data) and others produce a reduction in temperate forests. Elucidation of the cause of such differences is a focus of the current phase of the Palaeoclimate Modelling Intercomparison Project.

Results of PMIP2 coupled simulations of the mid-Holocene and Last Glacial Maximum, Part 2: feedbacks with emphasis on the location of the ITCZ and mid- and high latitudes heat budget

A set of coupled ocean-atmosphere(-vegetation) simulations using state of the art climate models is now available for the Last Glacial Maximum (LGM) and the Mid-Holocene (MH) through the second phase of the Paleoclimate Modeling Intercomparison Project (PMIP2). Here we quantify the latitudinal shift of the location of the Intertropical Convergence Zone (ITCZ) in the tropical regions during boreal summer and the change in precipitation in the northern part of the ITCZ. For both periods the shift is more pronounced over the continents and East Asia. The maritime continent is the region where the largest spread is found between models. We also clearly establish that the larger the increase in the meridional temperature gradient in the tropical Atlantic during summer at the MH, the larger the change in precipitation over West Africa. The vegetation feedback is however not as large as found in previous studies, probably due to model differences in the control simulation. Finally, we show that the feedback from snow and sea-ice at mid and high latitudes contributes for half of the cooling in the Northern Hemisphere for the LGM, with the remaining being achieved by the reduced CO2 and water vapour in the atmosphere. For the MH the snow and albedo feedbacks strengthen the spring cooling and enhance the boreal summer warming, whereas water vapour reinforces the late summer warming. These feedbacks are modest in the Southern Hemisphere. For the LGM most of the surface cooling is due to CO2 and water vapour.

Results of PMIP2 coupled simulations of the mid-Holocene and Last Glacial Maximum, Part 1: experiments and large-scale features

A set of coupled ocean-atmosphere simulations using state of the art climate models is now available for the Last Glacial Maximum and the Mid-Holocene through the second phase of the Paleoclimate Modeling Intercomparison Project (PMIP2). This study presents the large-scale features of the simulated climates and compares the new model results to those of the atmospheric models from the first phase of the PMIP, for which sea surface temperature was prescribed or computed using simple slab ocean formulations. We consider the large-scale features of the climate change, pointing out some of the major differences between the different sets of experiments. We show in particular that systematic differences between PMIP1 and PMIP2 simulations are due to the interactive ocean, such as the amplification of the African monsoon at the Mid-Holocene or the change in precipitation in mid-latitudes at the LGM. Also the PMIP2 simulations are in general in better agreement with data than PMIP1 simulations.