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.

Chronic systemic therapy with low-dose morpholino oligomers ameliorates the pathology and normalizes locomotor behavior in mdx Mice

The administration of antisense oligonucleotides (AOs) to skip one or more exons in mutated forms of the DMD gene and so restore the reading frame of the transcript is one of the most promising approaches to treat Duchenne muscular dystrophy (DMD). At present, preclinical studies demonstrating the efficacy and safety of long-term AO administration have not been conducted. Furthermore, it is essential to determine the minimal effective dose and frequency of administration. In this study, two different low doses (LDs) of phosphorodiamidate morpholino oligomer (PMO) designed to skip the mutated exon 23 in the mdx dystrophic mouse were administered for up to 12 months. Mice treated for 50 weeks showed a substantial dose-related amelioration of the pathology, particularly in the diaphragm. Moreover, the generalized physical activity was profoundly enhanced compared to untreated mdx mice showing that widespread, albeit partial, dystrophin expression restores the normal activity in mdx mice. Our results show for the first time that a chronic long-term administration of LDs of unmodified PMO, equivalent to doses in use in DMD boys, is safe, significantly ameliorates the muscular dystrophic phenotype and improves the activity of dystrophin-deficient mice, thus encouraging the further clinical translation of this approach in humans.

Normative, systemic and procedural aspects: a review of indicator-based sustainability assessments in agriculture

Methods for assessing the sustainability of agricultural systems do often not fully (i) take into account the multifunctionality of agriculture, (ii) include multidimensionality, (iii) utilize and implement the assessment knowledge and (iv) identify conflicting goals and trade-offs. This chapter reviews seven recently developed multidisciplinary indicator-based assessment methods with respect to their contribution to these shortcomings. All approaches include (1) normative aspects such as goal setting, (2) systemic aspects such as a specification of scale of analysis and (3) a reproducible structure of the approach. The approaches can be categorized into three typologies: first, top-down farm assessments, which focus on field or farm assessment; second, top-down regional assessments, which assess the on-farm and the regional effects; and third, bottom-up, integrated participatory or transdisciplinary approaches, which focus on a regional scale. Our analysis shows that the bottom-up, integrated participatory or transdisciplinary approaches seem to better overcome the four shortcomings mentioned above.

International office investment in global cities: the production of financial space and systemic risk

The paper explores the relationships between UK commercial real estate and regional economic development as a foundation for the analysis of the role of real estate investment in local economic development. Linkages between economic growth, development, real estate performance and investment allocations are documented. Long-run regional property performance is not the product of long-run economic growth, and weakly related to indicators of long-run supply and demand. Changes in regional portfolio weights seem driven by neither market performance nor underlying fundamentals. In the short run, regional investment shifts show no clear leads or lags with market performance.

Theology and politics in Richard Hooker's thought

Although Richard Hooker’s private attitudes were clericalist and authoritarian, his constitutional theory subordinated clergymen to laymen and monarchy to parliamentary statute. This article explains why his political ideas were nonetheless appropriate to his presumed religious purposes. It notes a very intimate connection between his teleological conception of a law and his hostility towards conventional high Calvinist ideas about predestination. The most significant anomaly within his broadly Aristotelian world-view was his belief that politics is nothing but a means to cope with sin. This too can be linked to his religious ends, but it creates an ambiguity that made his doctrines usable by Locke.

Unwritten law in Hobbesian political thought

In Hobbesian terminology, ‘unwritten laws’ are natural laws enforced within a polity, by a non-sovereign judge, without some previous public promulgation. This article discusses the idea in the light of successive Hobbesian accounts of ‘law’ and ‘obligation’. Between De Cive and Leviathan, Hobbes dropped the idea that natural law is strictly speaking law, but he continued to believe unwritten laws must form a part of any legal system. He was unable to explain how such a law could claim a legal status. His loyalty to the notion, in spite of all the trouble that it caused, is a sign of his belief that moral knowledge is readily accessible to all.

Dietary supplementation with Bifidobacterium lactis NCC2818 from weaning reduces local immunoglobulin production in lymphoid-associated tissues but increases systemic antibodies in healthy neonates

Weaning is associated with a major shift in the microbial community of the intestine, and this instability may make it more acquiescent than the adult microbiota to long-term changes. Modulation achieved through dietary interventions may have potentially beneficial effects on the developing immune system, which is driven primarily by the microbiota. The specific aim of the present study was to determine whether immune development could be modified by dietary supplementation with the human probiotic Bifidobacterium lactis NCC2818 in a tractable model of weaning in infants. Piglets were reared by their mothers before being weaned onto a solid diet supplemented with B. lactis NCC2818, while sibling controls did not receive supplementation. Probiotic supplementation resulted in a reduction in IgA (P,0·0005) and IgM (P,0·009) production by mucosal tissues but had no effect on IgG production (P.0·05). Probiotic- supplemented pigs had more mast cells than unsupplemented littermates (P,0·0001), although numbers in both groups were low. In addition, the supplemented piglets made stronger serum IgG responses to fed and injected antigens (P,0·05). The present findings are consistent with B. lactis NCC2818 reducing intestinal permeability induced by weaning, and suggest that the piglet is a valuable intermediate between rodent models and human infants. The results also strongly suggest that measures of the effect of probiotic supplementation on the immune system need to be interpreted carefully as proxy measures of health benefit. However, they are useful in developing an understanding of the mechanism of action of probiotic strains, an important factor in predicting favourable health outcomes of nutritional intervention.

Language and thought in bilinguals: the case of grammatical number and nonverbal classification preferences

Recent research shows that speakers of languages with obligatory plural marking (English) preferentially categorize objects based on common shape, whereas speakers of nonplural-marking classifier languages (Yucatec and Japanese) preferentially categorize objects based on common material. The current study extends that investigation to the domain of bilingualism. Japanese and English monolinguals, and Japanese–English bilinguals were asked to match novel objects based on either common shape or color. Results showed that English monolinguals selected shape significantly more than Japanese monolinguals, whereas the bilinguals shifted their cognitive preferences as a function of their second language proficiency. The implications of these findings for conceptual representation and cognitive processing in bilinguals are discussed.

Max Weber in the thought of Edward Shils (1910–1995) and Ernest Gellner (1925–1995): the paradox of two Weberian approaches to the understanding of nations and nationalism?

This article traces the paradoxical impact of Weber's oeuvre on two major scholars of nationalism, Ernest Gellner and Edward Shils. Both these scholars died in 1995, leaving behind a rich corpus of writings on the nation and nationalism, much of which was inspired by Max Weber. The paradox is that although neither scholar accepted Weber's sceptical attitude to the concept of ‘nation’, they both used his other major concepts, such as ‘rationality’, ‘disenchantment’, ‘unintended consequences’, the ‘ethic of responsibility’ and ‘charisma’, in their very analyses of the nation and nationalism. And they both saw, each in his own way, the nation and nationalism as constitutive elements of modern societies. However, the paradox ceases being a paradox if one sees the integration, by Shils and Gellner, of concepts of the nation and of nationalism in the analysis of modernity, as a development of Weber's ideas.

Endocannabinoids, FOXO and the metabolic syndrome: redox, function and tipping point--the view from two systems

The endocannabinoid system (ECS) was only 'discovered' in the 1990s. Since then, many new ligands have been identified, as well as many new intracellular targets--ranging from the PPARs, to mitochondria, to lipid rafts. It was thought that blocking the CB-1 receptor might reverse obesity and the metabolic syndrome. This was based on the idea that the ECS was dysfunctional in these conditions. This has met with limited success. The reason may be that the ECS is a homeostatic system, which integrates energy seeking and storage behaviour with resistance to oxidative stress. It could be viewed as having thrifty actions. Thriftiness is an innate property of life, which is programmed to a set point by both environment and genetics, resulting in an epigenotype perfectly adapted to its environment. This thrifty set point can be modulated by hormetic stimuli, such as exercise, cold and plant micronutrients. We have proposed that the physiological and protective insulin resistance that underlies thriftiness encapsulates something called 'redox thriftiness', whereby insulin resistance is determined by the ability to resist oxidative stress. Modern man has removed most hormetic stimuli and replaced them with a calorific sedentary lifestyle, leading to increased risk of metabolic inflexibility. We suggest that there is a tipping point where lipotoxicity in adipose and hepatic cells induces mild inflammation, which switches thrifty insulin resistance to inflammation-driven insulin resistance. To understand this, we propose that the metabolic syndrome could be seen from the viewpoint of the ECS, the mitochondrion and the FOXO group of transcription factors. FOXO has many thrifty actions, including increasing insulin resistance and appetite, suppressing oxidative stress and shifting the organism towards using fatty acids. In concert with factors such as PGC-1, they also modify mitochondrial function and biogenesis. Hence, the ECS and FOXO may interact at many points; one of which may be via intracellular redox signalling. As cannabinoids have been shown to modulate reactive oxygen species production, it is possible that they can upregulate anti-oxidant defences. This suggests they may have an 'endohormetic' signalling function. The tipping point into the metabolic syndrome may be the result of a chronic lack of hormetic stimuli (in particular, physical activity), and thus, stimulus for PGC-1, with a resultant reduction in mitochondrial function and a reduced lipid capacitance. This, in the context of a positive calorie environment, will result in increased visceral adipose tissue volume, abnormal ectopic fat content and systemic inflammation. This would worsen the inflammatory-driven pathological insulin resistance and inability to deal with lipids. The resultant oxidative stress may therefore drive a compensatory anti-oxidative response epitomised by the ECS and FOXO. Thus, although blocking the ECS (e.g. via rimonabant) may induce temporary weight loss, it may compromise long-term stress resistance. Clues about how to modulate the system more safely are emerging from observations that some polyphenols, such as resveratrol and possibly, some phytocannabinoids, can modulate mitochondrial function and might improve resistance to a modern lifestyle.

Pause for thought

The recent slowdown (or 'pause') in global surface temperature rise is a hot topic for climate scientists and the wider public. We discuss how climate scientists have tried to communicate the pause and suggest that 'many-to-many' communication offers a key opportunity to directly engage with the public.