The effects of difficulty and gain versus loss on vocal physiology and acoustics

To examine the basis of emotional changes to the voice, physiological and electroglottal measures were combined with acoustic speech analysis of 30 men performing a computer task in which they lost or gained points under two levels of difficulty. Predictions of the main effects of difficulty and reward on the voice were not borne out by the data. Instead, vocal changes depended largely on interactions between gain versus loss and difficulty. The rate at which the vocal folds open and close (fundamental frequency; f0) was higher for loss than for gain when difficulty was high, but not when difficulty was low. Electroglottal measures revealed that f0 changes corresponded to shorter glottal open times for the loss conditions. Longer closed and shorter open phases were consistent with raised laryngeal tension in difficult loss conditions. Similarly, skin conductance indicated higher sympathetic arousal in loss than gain conditions, particularly when difficulty was high. The results provide evidence of the physiological basis of affective vocal responses, confirming the utility of measuring physiology and voice in the study of emotion.

Early women law students at Cambridge and Oxford

This article examines the hitherto neglected history of the twelve women who studied law at Cambridge and Oxford in the years up to 1900. It concludes that the reason why so little has been written about them is, first, because women's experience has been routinely ignored in accounts of legal education ( and in history generally) and, second, because their entry to the university law schools was accomplished with very little fuss or opposition. This in turn was due not only to the fact that the law professors were generally sympathetic to higher education for women but also because the women themselves did not challenge university traditions or the men's curriculum.

Medusa, Antaeus, and Caesar Libycus

Although it is well known that Lucan’s Libya is a wild and threatening place, its threat is not restricted to indigenous people, places and things, such as Hannibal, Cleopatra, the Syrtes, or the desert with its catalogue of horrifying snakes. He also associates Libya with anti-Republican Romans, above all Julius Caesar, who endangers the Republic with his excessive, animalistic energy and resembles the continent where he is trapped in the final book. Although the gods as characters are removed from the world of the Bellum Civile, Lucan allows supernatural traces to linger in particular locations such as the Gallic grove in Book 3 or Thessaly in Book 6. Libya is by far the greatest of these reservoirs of frightening myth and fantasy, which do violence to the historical credibility of the narrative, just as Libya itself is presented as the origin or conduit of a number of historical characters who assault Italy and Europe. Lucan’s two mythic narratives (Antaeus in Book 4 and Medusa in Book 9) are essential parts of the hostile Libyan landscape, but in very different ways. The male Antaeus, associated with lions, is connected with a region of solid rock where he was destroyed. The female Medusa, associated with snakes, is connected with a region of shifting sands where she left a deadly, everlasting legacy. To complicate matters further, even though Medusa’s snakes represent the annihilation of the Republican self, the logic of the narrative is undermined and there is even a sympathetic subtext. As part of Libya’s historical and mythical legacy, these stories reveal that for Lucan, historical epic is linked with Republicanism, but mythical epic is in the service of dictatorship.

Differential effects of thyroid hormone manipulation and ß adrenoceptor agonist administration on uncoupling protein mRNA abundance in adipose tissue and thermoregulation in neonatal pigs

We have shown that there is significant disparity in the expression of uncoupling proteins (UCP) 2 and 3 between modern-commercial and ancient-Meishan porcine genotypes, commercial pigs also have higher plasma triiodothyronine (T(3)) in on the first day of life. T(3) and the sympathetic nervous system are both known to regulate UCPs in rodents and humans; their role in regulating these proteins in the pig is unknown. This study examined whether thyroid hormone manipulation or administration of a selective beta3 adrenoceptor agonist (ZD) influenced plasma hormones, colonic temperature and UCP expression in adipose tissue of two breeds of pig. To mimic the differences observed in thyroid hormone status, piglets from Meishan and commercial litters were randomly assigned to control (1 ml/kg water), T(3) (10 mg/kg) (Meishan only), methimazole (a commonly used antithyroid drug) (50 mg/kg) (commercial only) or ZD (10 mg/kg) oral administration for the first 4 days of postnatal life. Adipose tissue UCP2/3 mRNA abundance was measured on day 4 using PCR. T(3) administration raised plasma T(3) concentrations and increased colonic temperature on day 4. UCP3 mRNA abundance was higher in Meishan, than commercial piglets (p = 0.042) and was downregulated following T(3) administration (p = 0.014). Irrespective of genotype, ZD increased UCP2 mRNA abundance (Meishan p = 0.05, commercial p = 0.03). Expression of neither UCP2 nor 3 was related to colonic temperature, regardless of treatment. In conclusion, we have demonstrated a dissociation between thyroid hormones and the sympathetic nervous system in the regulation of UCPs in porcine adipose tissue. We have also suggested that expression of adipose tissue UCP2 and 3 are not related to body temperature in piglets.

Investigating the effects of predator removal and habitat management on nest success and breeding population size of a farmland passerine: a case study

Passerines are especially vulnerable to predation at the pre-independence stage. Although the role of nest success in British farmland passerine declines is contentious, improvement in nest success through sympathetic management could play a role in their reversal. Because habitat is known to interact with predation, management options for mitigation will need to consider effects of nest predation. We present results from an observational study of a population of Common Blackbird Turdus merula on a farm which has experienced a range of agri-environment and game-management options, including a period with nest predator control, as a case study to address some of these issues. We used an information theoretic model comparison procedure to look for evidence of interactions between habitat and nest predation, and then asked whether habitat management and nest predator abundances could explain population trends at the site through their effects on nest success. Interactions were detected between measures of predator abundance and habitat variables, and these varied with nest stage - habitat within the vicinity of the nest appeared to be important at the egg stage, and nest-placement characteristics were important at the nestling stage. Although predator control appeared to have a positive influence on Blackbird breeding population size, the non-experimental set-up meant we could not eliminate other potential explanations. Variation in breeding population size did not appear to be influenced by variation in nest success alone. Our study demonstrates that observational data can only go so far in detection of such effects, and we discuss how it might be taken further. Agri-environment and game-management techniques are likely to influence nest predation pressure on farmland passerines, but the patterns, mechanisms and importance to population processes remain not wholly understood.

Investigating the effects of predator removal and habitat management on nest success and breeding population size of a farmland passerine: a case study

Passerines are especially vulnerable to predation at the pre-independence stage. Although the role of nest success in British farmland passerine declines is contentious, improvement in nest success through sympathetic management could play a role in their reversal. Because habitat is known to interact with predation, management options for mitigation will need to consider effects of nest predation. We present results from an observational study of a population of Common Blackbird Turdus merula on a farm which has experienced a range of agri-environment and game-management options, including a period with nest predator control, as a case study to address some of these issues. We used an information theoretic model comparison procedure to look for evidence of interactions between habitat and nest predation, and then asked whether habitat management and nest predator abundances could explain population trends at the site through their effects on nest success. Interactions were detected between measures of predator abundance and habitat variables, and these varied with nest stage - habitat within the vicinity of the nest appeared to be important at the egg stage, and nest-placement characteristics were important at the nestling stage. Although predator control appeared to have a positive influence on Blackbird breeding population size, the non-experimental set-up meant we could not eliminate other potential explanations. Variation in breeding population size did not appear to be influenced by variation in nest success alone. Our study demonstrates that observational data can only go so far in detection of such effects, and we discuss how it might be taken further. Agri-environment and game-management techniques are likely to influence nest predation pressure on farmland passerines, but the patterns, mechanisms and importance to population processes remain not wholly understood.

The role played by the interaction between genetic factors and attachment in the stress response in infancy

Background: The importance of understanding which environmental and biological factors are involved in determining individual differences in physiological response to stress is widely recognized, given the impact that stress has on physical and mental health. Methods: The child-mother attachment relationship and some genetic polymorphisms (5-HTTLPR, COMT and GABRA6) were tested as predictors of salivary cortisol and alpha amylase concentrations, two biomarkers of hypothalamic-pituitary-adrenocortical (HPA) axis and sympathetic adrenomedullary (SAM) system activity, during the Strange Situation (SS) procedure in a sample of more than 100 healthy infants, aged 12 to 18 months. Results: Individual differences in alpha amylase response to separation were predicted by security of attachment in interaction with 5-HTTLPR and GABRA6 genetic polymorphisms, whereas alpha amylase basal levels were predicted by COMT x attachment interaction. No significant effect of attachment, genetics and their interaction on cortisol activity emerged. Conclusions: These results help to disentangle the role played by both genetic and environmental factors in determining individual differences in stress response in infancy. The results also shed light on the suggestion that HPA and SAM systems are likely to have different characteristic responses to stress.

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.

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.

Chaucer's presence in songes and sonettes

In an elegy to Wyatt published in Tottel’s Miscellany, Surrey claims that Wyatt ‘reft Chaucer the glory of his wit’. This statement, which both lauds and resists Chaucer, is a microcosm of the way Chaucer is treated throughout the Miscellany. In examining the collection’s paradoxical attitude to Chaucer, this essay focuses particularly on the Squire’s Tale, the Franklin’s Tale, Anelida and Arcite, the Legend of Good Women, and several short lyrics. In its interest in courtly love poetry and Petrarch, the Miscellany follows a trajectory in English poetry set by Chaucer. Its courtly verse is saturated with words, phrases, and tropes from his poetry. Rhyme royal, which he introduced into English poetry, is widely used. The Canterbury Tales has been fully assimilated and can be referred to allusively with the same confidence of the audience’s knowledge as is the case when referring to classical myth; in Wyatt’s ‘Myne owne Jhon Poins’, the speaker, disclaiming deceitfulness, says that he cannot ‘say that Pan/ Passeth Appollo in musike manifold:/ Praise syr Topas for a noble tale,/ And scorne the story that the knight tolde’ (lines 48-50). However, Chaucer’s poetry is also downplayed and contested in the Miscellany. ‘Truth’, the only poem of his which appears in the volume, is disingenuously placed in the ‘Uncertain Authors’ section. In addition, some of the most important elements of his work are strongly resisted in the Miscellany, either ignored, dismissed or challenged. These elements include Chaucer’s interest in variety of voice, his sympathetic engagement with women, particularly wronged women, and his interest in female speech and particularly female complaint. The Miscellany, by contrast, is dominated by male-voiced lyrics preoccupied with the pain inflicted on the lover by a lady who is frequently unfeeling, cruel, or faithless. Chaucer’s frequent focus on the cynical seduction and betrayal of female by male is reversed in the Miscellany, and the language and metaphors he uses to express male cruelty (e.g. the word ‘newfangleness’ and images of hooks, nets and traps) are usurped to describe the lady’s cruelty to the suffering lover. On occasion, poems in the Miscellany challenge specific Chaucerian texts; ‘On His Love Named White’ throws down a gauntlet to The Book of the Duchess, while two of Surrey’s poems implicitly take issue with the female falcon’s voice in the Squire’s Tale, giving the deceitful tercelet the opportunity to shout down the falcon’s charges. The essay thus shows that in many respects Tottel’s Miscellany is only superficially Chaucerian, and that it both passively and actively takes issue with Chaucer’s work.

Harringtonian virtue: Harrington, Machiavelli, and the method of the 'Moment'

This article presents a reinterpretation of James Harrington's writings. It takes issue with J. G. A. Pocock's reading, which treats him as importing into England a Machiavellian ‘language of political thought’. This reading is the basis of Pocock's stress on the republicanism of eighteenth-century opposition values. Harrington's writings were in fact a most implausible channel for such ideas. His outlook owed much to Stoicism. Unlike the Florentine, he admired the contemplative life; was sympathetic to commerce; and was relaxed about the threat of ‘corruption’ (a concept that he did not understand). These views can be associated with his apparent aims: the preservation of a national church with a salaried but politically impotent clergy; and the restoration of the royalist gentry to a leading role in English politics. Pocock's hypothesis is shown to be conditioned by his method; its weaknesses reflect some difficulties inherent in the notion of ‘languages of thought’.

Sharing power? Prospects for a U.S. concert-balance strategy

The Pax Americana and the grand strategy of hegemony (or “Primacy”) that underpins it may be becoming unsustainable. Particularly in the wake of exhausting wars, the Global Financial Crisis, and the shift of wealth from West to East, it may no longer be possible or prudent for the United States to act as the unipolar sheriff or guardian of a world order. But how viable are the alternatives, and what difficulties will these alternatives entail in their design and execution? This analysis offers a sympathetic but critical analysis of alternative U.S. National Security Strategies of “retrenchment” that critics of American diplomacy offer. In these strategies, the United States would anticipate the coming of a more multipolar world and organize its behavior around the dual principles of “concert” and “balance,” seeking a collaborative relationship with other great powers, while being prepared to counterbalance any hostile aggressor that threatens world order. The proponents of such strategies argue that by scaling back its global military presence and its commitments, the United States can trade prestige for security, shift burdens, and attain a more free hand. To support this theory, they often look to the 19th-century concert of Europe as a model of a successful security regime and to general theories about the natural balancing behavior of states. This monograph examines this precedent and measures its usefulness for contemporary statecraft to identify how great power concerts are sustained and how they break down. The project also applies competing theories to how states might behave if world politics are in transition: Will they balance, bandwagon, or hedge? This demonstrates the multiple possible futures that could shape and be shaped by a new strategy. viii A new strategy based on an acceptance of multipolarity and the limits of power is prudent. There is scope for such a shift. The convergence of several trends—including transnational problems needing collaborative efforts, the military advantages of defenders, the reluctance of states to engage in unbridled competition, and hegemony fatigue among the American people—means that an opportunity exists internationally and at home for a shift to a new strategy. But a Concert-Balance strategy will still need to deal with several potential dilemmas. These include the difficulty of reconciling competitive balancing with cooperative concerts, the limits of balancing without a forward-reaching onshore military capability, possible unanticipated consequences such as a rise in regional power competition or the emergence of blocs (such as a Chinese East Asia or an Iranian Gulf), and the challenge of sustaining domestic political support for a strategy that voluntarily abdicates world leadership. These difficulties can be mitigated, but they must be met with pragmatic and gradual implementation as well as elegant theorizing and the need to avoid swapping one ironclad, doctrinaire grand strategy for another.

Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer

Duchenne muscular dystrophy is a fatal muscle-wasting disorder. Lack of dystrophin compromises the integrity of the sarcolemma and results in myofibers that are highly prone to contraction-induced injury. Recombinant adenoassociated virus (rAAV)-mediated dystrophin gene transfer strategies to muscle for the treatment of Duchenne muscular dystrophy (DMD) have been limited by the small cloning capacity of rAAV vectors and high titers necessary to achieve efficient systemic gene transfer. In this study, we assess the impact of codon optimization on microdystrophin (ΔAB/R3-R18/ΔCT) expression and function in the mdx mouse and compare the function of two different configurations of codon-optimized microdystrophin genes (ΔAB/R3-R18/ΔCT and ΔR4-R23/ΔCT) under the control of a muscle-restrictive promoter (Spc5-12). Codon optimization of microdystrophin significantly increases levels of microdystrophin mRNA and protein after intramuscular and systemic administration of plasmid DNA or rAAV2/8. Physiological assessment demonstrates that codon optimization of ΔAB/R3-R18/ΔCT results in significant improvement in specific force, but does not improve resistance to eccentric contractions compared with noncodon-optimized ΔAB/ R3-R18/ΔCT. However, codon-optimized microdystrophin ΔR4-R23/ΔCT completely restored specific force generation and provided substantial protection from contraction-induced injury. These results demonstrate that codon optimization of microdystrophin under the control of a muscle-specific promoter can significantly improve expression levels such that reduced titers of rAAV vectors will be required for efficient systemic administration.

Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice. Level of α1-Syntrophin and α-Dystrobrevin in Skeletal Muscles of mdx Mice

Duchenne muscular dystrophy is a severe X-linked inherited muscle wasting disorder caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vectors have been extensively used to deliver genes efficiently for dystrophin expression in skeletal muscles. To overcome limited packaging capacity of AAV vectors (<5 kb), truncated recombinant microdystrophin genes with deletions of most of rod and carboxyl-terminal (CT) domains of dystrophin have been developed. We have previously shown the efficiency of mRNA sequence–optimized microdystrophin (ΔR4-23/ΔCT, called MD1) with deletion of spectrin-like repeat domain 4 to 23 and CT domain in ameliorating the pathology of dystrophic mdx mice. However, the CT domain of dystrophin is thought to recruit part of the dystrophin-associated protein complex, which acts as a mediator of signalling between extracellular matrix and cytoskeleton in muscle fibers. In this study, we extended the ΔR4-23/ΔCT microdystrophin by incorporating helix 1 of the coiled-coil motif in the CT domain of dystrophin (MD2), which contains the α1-syntrophin and α-dystrobrevin binding sites. Intramuscular injection of AAV2/9 expressing CT domain–extended microdystrophin showed efficient dystrophin expression in tibialis anterior muscles of mdx mice. The presence of the CT domain of dystrophin in MD2 increased the recruitment of α1-syntrophin and α-dystrobrevin at the sarcolemma and significantly improved the muscle resistance to lengthening contraction–induced muscle damage in the mdx mice compared with MD1. These results suggest that the incorporation of helix 1 of the coiled-coil motif in the CT domain of dystrophin to the microdystrophins will substantially improve their efficiency in restoring muscle function in patients with Duchenne muscular dystrophy.

Bigger data for Big Data: from Twitter to brain-computer interface

We are sympathetic with Bentley et al’s attempt to encompass the wisdom of crowds in a generative model, but posit that success at using Big Data will include more sensitive measurements, more and more varied sources of information, as well as build from the indirect information available through technology, from ancillary technical features to data from brain-computer interface.