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The role of Raptor in adult skeletal muscle
Full text linkSkeletal muscle is the largest organ in the body comprising 40% of total body mass. Skeletal muscle mass is the result of an equilibrium between protein synthesis and protein breakdown. When protein synthesis overcomes protein degradation the result is muscle hypertrophy with increased fiber size. Better understanding of the signaling pathways controlling muscle mass and function is of great importance. Indeed so far there are no therapeutic approaches that can prevent or reduce muscle wasting, as seen in aging and muscular dystrophy. While various studies have identified important regulators of adult skeletal muscle mass, little is known about how these pathways can modulate muscle function. One of the main pathways regulating skeletal muscle is the Akt-mTOR pathway. Under anabolic conditions, mTOR is activated, leading to increased protein synthesis through the phosphorylation of S6K1 and 4EBP1. On the other hand, mTOR activation can also lead to the inhibition of protein degradation through the phosphorylation of Ulk1, which is involved in the autophagosome formation.
mTOR assembles into two distinct multiprotein complexes, namely the rapamycin-sensitive complex mTORC1 and the rapamycin-insensitive complex mTORC2. While mTORC2 is mainly involved in cytoskeleton reorganization, mTORC1 plays a role in cell growth and protein synthesis. One of the key members of the mTORC1 is a 150kDa protein called Raptor, which has been shown to be able to recruit mTOR substrates S6K1 and 4EBP1 on mTORC1, promoting their phosphorylation (Hara et al., 2002) (Kim et al., 2002).
Mice lacking Raptor only in skeletal muscle from birth show a pronounced myopathy leading to premature death (Bentzinger et al., 2008). However, treating adult mice with the specific mTORC1 inhibitor rapamycin does not lead to a myopathic phenotype and even improves muscle physiology in aged mice (Harrison et al., 2009). So, we wondered what happens if Raptor is deleted in adult skeletal muscle.
We, therefore, generated an inducible muscle-specific Raptor knock-out mouse line (HSA-Raptor ko).
One month of Raptor deletion in adult muscle does not affect muscle mass or muscle morphology. In addition, also muscle force production is comparable between control and knock-out animals, confirming that at this time point there are no myopathies.
Since in literature it has been reported that deletion of Raptor from birth leads to premature death around 5-6 months of age, we decided to monitor mice lifespan and body weight for a longer period after deletion. We observed that body weight during these months is unchanged between wt and Raptor ko mice, so we decided to sacrifice mice 7 months after the beginning of the treatment to assess muscle histology.
At this time point, muscles from Raptor ko mice showed signs of a muscle myopathy, with centronucleated fibers, a high number of small and large muscle fibers, central structures and inflammation. In addition, we observed that Raptor knock-out muscles show a huge amount of spontaneous fibrillation spikes at rest, suggesting the presence of denervated fibers. Furthermore, mitochondrial membrane potential and respiratory chain complex activity are impaired upon Raptor deletion. These features result in compromised muscle performance and exercise intolerance.
Moreover, while metabolic characteristics upon Raptor deletion shift from oxidative to glycolytic fibers with glycogen accumulation, structural properties reveal the opposite behaviour, with a shift from fast- to slow- twitch fibers. This is likely linked to the increased activity of calcineurin- NFAT pathway seen in Raptor ko muscles.
Since understanding the key players in the regulation of muscle mass can be of therapeutic interest, we wanted to understand the role of Raptor during Akt-induced hypertrophy. So, we generate an inducible muscle- specific Akt-Raptor ko mouse line.
Akt overexpression results in a strong increase in cross-sectional area of muscle fibers, which is only partially reduced upon Raptor deletion. Moreover, fiber hypertrophy is completely blunted when Akt-Raptor ko mice are treated with the mTORC1 inhibitor, rapamycin.
We also found that Akt-Raptor ko mice are significantly weaker than controls, meaning that Akt-induced hypertrophy in the absence of Raptor is not functional anymore. In addition, this effect is not reverted by rapamycin administration, as seen in Akt-S6K1 knock-out mice (Marabita et al., 2016)
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Custom-made 3D-printed boot as a model of disuse-induced atrophy in murine skeletal muscle
Full text linkSkeletal muscle atrophy is characterized by a decrease in muscle mass and strength caused by an imbalance in protein synthesis and degradation. This process naturally occurs upon reduced or absent physical activity, often related to illness, forced bed rest, or unhealthy lifestyles. Currently, no treatment is available for atrophy, and it can only be prevented by overloading exercise, causing severe problems for patients who cannot exercise due to chronic diseases, disabilities, or being bedridden. The two murine models commonly used to induce muscle atrophy are hindlimb suspension and ankle joint immobilization, both of which come with criticalities. The lack of treatments and the relevance of this atrophic process require a unilateral, safe, and robust model to induce muscle atrophy. In this work, we designed and developed a 3D-printed cast to be used for the study of disuse skeletal muscle atrophy. Applying two halves of the cast is non-invasive, producing little to no swelling or skin damage. The application of the cast induces, in 2-weeks immobilized leg, the activation of atrophy-related genes, causing a muscle weight loss up to 25% in the gastrocnemius muscle, and 31% in the soleus muscle of the immobilized leg compared to the control leg. The cross-sectional area of the fibers is decreased by 31% and 34% respectively, with a peculiar effect on fiber types. In the immobilized gastrocnemius, absolute muscle force is reduced by 38%, while normalized force is reduced by 16%. The contralateral leg did not show signs of overload or hypertrophy when compared to free roaming littermates, offering a good internal control over the immobilized limb. Upon removing the cast, the mice effectively recovered mass and force in 3 weeks
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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