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.

A multi-model analysis of the role of the ocean on the African and Indian monsoon during mid-Holocene

We investigate the role of the ocean feedback on the climate in response to insolation forcing during the mid-Holocene (6,000 year BP) using results from seven coupled ocean–atmosphere general circulation models. We examine how the dipole in late summer sea-surface temperature (SST) anomalies in the tropical Atlantic increases the length of the African monsoon, how this dipole structure is created and maintained, and how the late summer SST warming in the northwest Indian Ocean affects the monsoon retreat in this sector. Similar mechanisms are found in all of the models, including a strong wind evaporation feedback and changes in the mixed layer depth that enhance the insolation forcing, as well as increased Ekman transport in the Atlantic that sharpens the Atlantic dipole pattern. We also consider changes in interannual variability over West Africa and the Indian Ocean. The teleconnection between variations in SST and Sahelian precipitation favor a larger impact of the Atlantic dipole mode in this region. In the Indian Ocean, the strengthening of the Indian dipole structure in autumn has a damping effect on the Indian dipole mode at the interannual time scale

Global monsoons in the mid-Holocene and oceanic feedback

The response of the six major summer monsoon systems (the North American monsoon, the northern Africa monsoon, the Asia monsoon, the northern Australasian monsoon, the South America monsoon and the southern Africa monsoon) to mid-Holocene orbital forcing has been investigated using a coupled ocean–atmosphere general circulation model (FOAM), with the focus on the distinct roles of the direct insolation forcing and oceanic feedback. The simulation result is also found to compare well with the NCAR CSM. The direct effects of the change in insolation produce an enhancement of the Northern Hemisphere monsoons and a reduction of the Southern Hemisphere monsoons. Ocean feedbacks produce a further enhancement of the northern Africa monsoon and the North American monsoon. However, ocean feedbacks appear to weaken the Asia monsoon, although the overall effect (direct insolation forcing plus ocean feedback) remains a strengthened monsoon. The impact of ocean feedbacks on the South American and southern African monsoons is relatively small, and therefore these regions, especially the South America, experienced a reduced monsoon regime compared to present. However, there is a strong ocean feedback on the northern Australian monsoon that negates the direct effects of orbital changes and results in a strengthening of austral summer monsoon precipitation in this region. A new synthesis is made for mid-Holocene paleoenvironmental records and is compared with the model simulations. Overall, model simulations produce changes in regional climates that are generally consistent with paleoenvironmental observations.

Mid-Holocene climates of the Americas: a dynamical response to changed seasonality

Simulations of the climatic response to mid-Holocene (6 ka BP) orbital forcing with two coupled ocean–atmosphere models (FOAM and CSM) show enhancement of monsoonal precipitation in parts of the American Southwest, Central America and northernmost South America during Northern Hemisphere summer. The enhanced onshore flow that brings precipitation into Central America is caused by a northward displacement of the inter-tropical convergence zone, driven by cooling of the equatorial and warming of the northern subtropical and mid-latitude ocean. Ocean feedbacks also enhance precipitation over the American Southwest, although the increase in monsoon precipitation there is largely driven by increases in land-surface temperature. The northward shift in the equatorial precipitation band that causes enhanced precipitation in Central America and the American Southwest has a negative feedback effect on monsoonal precipitation in northern South America. The simulations demonstrate that mid-Holocene aridity in the mid-continent of North America is dynamically linked to the orbitally induced enhancement of the summer monsoon in the American Southwest, with a spatial structure (wet in the Southwest and dry in the mid-continent) similar to that found in strong monsoon years today. Changes in winter precipitation along the west coast of North America, in Central America and along the Gulf Coast, caused by southward-displacement of the westerly storm tracks, indicate that changes in the Northern Hemisphere winter monsoon also play a role in regional climate changes during the mid-Holocene. Although the simulations with FOAM and CSM differ in detail, the general mechanisms and patterns are common to both. The model results thus provide a coherent dynamical explanation for regional patterns of increased or decreased aridity shown by vegetation, lake status and aeolian data from the Americas

A simulation of the last glacial maximum climate using the NCAR-CCSM

The National Center for Atmospheric Research-Community Climate System Model (NCAR-CCSM) is used in a coupled atmosphere–ocean–sea-ice simulation of the Last Glacial Maximum (LGM, around 21,000 years ago) climate. In the tropics, the simulation shows a moderate cooling of 3 °C over land and 2 °C in the ocean in zonal average. This cooling is about 1 °C cooler than the CLIMAP sea surface temperatures (SSTs) but consistent with recent estimates of both land and sea surface temperature changes. Subtropical waters are cooled by 2–2.5 °C, also in agreement with recent estimates. The simulated oceanic thermohaline circulation at the LGM is not only shallower but also weaker than the modern with a migration of deep-water formation site in the North Atlantic as suggested by the paleoceanographic evidences. The simulated northward flow of Antarctic Bottom Water (AABW) is enhanced. These deep circulation changes are attributable to the increased surface density flux in the Southern Ocean caused by sea-ice expansion at the LGM. Both the Gulf Stream and the Kuroshio are intensified due to the overall increase of wind stress over the subtropical oceans. The intensified zonal wind stress and southward shift of its maximum in the Southern Ocean effectively enhances the transport of the Antarctic Circumpolar Current (ACC) by more than 50%. Simulated SSTs are lowered by up to 8 °C in the midlatitudes. Simulated conditions in the North Atlantic are warmer and with less sea-ice than indicated by CLIMAP again, in agreement with more recent estimates. The increased meridional SST gradient at the LGM results in an enhanced Hadley Circulation and increased midlatitude storm track precipitation. The increased baroclinic storm activity also intensifies the meridional atmospheric heat transport. A sensitivity experiment shows that about half of the simulated tropical cooling at the LGM originates from reduced atmospheric concentrations of greenhouse gases.