Vagal nerve stimulation therapy: what is being stimulated?

Vagal nerve stimulation in cardiac therapy involves delivering electrical current to the vagal sympathetic complex in patients experiencing heart failure. The therapy has shown promise but the mechanisms by which any benefit accrues is not understood. In this paper we model the response to increased levels of stimulation of individual components of the vagal sympathetic complex as a differential activation of each component in the control of heart rate. The model provides insight beyond what is available in the animal experiment in as much as allowing the simultaneous assessment of neuronal activity throughout the cardiac neural axis. The results indicate that there is sensitivity of the neural network to low level subthreshold stimulation. This leads us to propose that the chronic effects of vagal nerve stimulation therapy lie within the indirect pathways that target intrinsic cardiac local circuit neurons because they have the capacity for plasticity

Who Writes the Rules for Hostile Takeovers, and Why? The Peculiar Divergence of US and UK Takeover Regulation

Hostile takeovers are commonly thought to play a key role in rendering managers accountable to dispersed shareholders in the "Anglo-American " system of corporate governance. Yet surprisingly little attention has been paid to the very significant differences in takeover regulation between the two most prominent jurisdictions. In the United Kingdom, defensive tactics by target managers are prohibited, whereas Delaware law gives U.S. managers a good deal of room to maneuver. Existing accounts of this difference focus on alleged pathologies in competitive federalism in the United States. In contrast, we focus on the "supply-side" of rule production by examining the evolution of the two regimes from a public choice perspective. We suggest that the content of the rules has been crucially influenced by differences in the mode of regulation. In the United Kingdom, self-regulation of takeovers has led to a regime largely driven by the interests of institutional investors, whereas the dynamics of judicial law-making in the United States have benefited managers by making it relatively difficult for shareholders to influence the rules. Moreover, it was never possible for Wall Street to "privatize" takeovers in the same way as the City of London, because U.S. federal regulation in the 1930s both pre-empted self-regulation and restricted the ability of institutional investors to coordinate

Corporate Ownership Structure and the Evolution of Bankruptcy Law: Lessons from the United Kingdom

The corporate world today subdivides into rival systems of dispersed and concentrated ownership, each characterized by different corporate governance structures. The United States falls into the former category, whereas major industrial rivals such as Japan and Germany are members of the latter. The past decade has seen intense academic debate over possible explanations for the different systems of ownership and control in key developed economies. Anecdotal evidence suggesting that market forces may be serving to destabilize traditional business structures and foster some form of convergence in a U.S. direction has given the controversy powerful current relevance. For those seeking to account for the existence of rival systems of dispersed and concentrated ownership, the United Kingdom has proved to be something of a problem child. Britain is a companion to the United States in the dispersed ownership category since, as is the case in the U.S., publicly quoted companies are a pivotal feature of the corporate economy, and large business enterprises typically have diffuse ownership structures. Given the similarities between the two countries, a logical way to test the various theories offered to account for the configuration of America\u27s system of ownership and control is to see whether they have explanatory power in a British context. When this sort of analysis has been done, however, events occurring in the U.K. have tended to cast doubt upon each hypothesis. This has been the outcome, for instance, with theories concerning financial services regulation, political ideology, and minority shareholder protection. This Article\u27s purpose is to refer again to the British experience to test and refine an additional hypothesis that has been offered to explain why the corporate economy is organized differently in the U.S. than in countries such as Germany and Japan. Corporate bankruptcy, it has been said, is the crucial missing piece in understanding corporate governance. According to this thesis-an evolutionary account of corporate governance-a country\u27s system of bankruptcy law is either manager-driven or manager-displacing, with the former offering the executives of a financially troubled firm substantial scope to launch a rescue effort and the latter having a strong bias in favor of liquidation. The thinking, in very basic terms, is that a manager-driven bankruptcy regime complements dispersed share ownership, while its manager-displacing counterpart aligns with a governance regime where concentrated ownership prevails. Given the configuration of the U.K.\u27s system of ownership and control, this would imply that Britain should have a manager-driven bankruptcy system. As we will see, though, the country\u27s bankruptcy laws strongly protect lenders, and few British companies that end up in formal bankruptcy proceedings escape liquidation

Development and Validation of Molecular Markers for \u3cem\u3ePhytophthora medicaginis\u3c/em\u3e Resistance in Lucerne

Resistance to Phytophthora medicaginis is an essential attribute to incorporate into lucerne (Medicago sativa) cultivars which are likely to be grown on heavy soils or in conditions where the soil remains excessively wet for prolonged periods. Current breeding strategies rely on recurrent phenotypic selection to maintain adequate levels of resistance in newly developed synthetic cultivars. However, little is known about the source or mechanism(s) of genetic resistance operating in the cultivar. A genetic linkage map was generated from a tetraploid M. sativa population using SSR markers anchored to existing genetic and physical maps. Large effect QTL were identified on linkage groups 2, 5, 6 and 7, each of which contributed between 11-30% of the phenotypic variation. Evaluation of the marker-trait associations in another sampling of the same population was undertaken, using a different isolate of P. medicaginis. The findings indicate that in the lucerne genotype examined in this study, a network of interactions involving at least three common loci, contribute to resistance to P. medicaginis. An alignment of the resistance loci identified in this study with those previously identified provided a framework for cataloguing the diversity of resistance loci present in lucerne, and will be used to guide future lucerne breeding efforts

Vagal Nerve Stimulation Therapy: What Is Being Stimulated?

Vagal nerve stimulation in cardiac therapy involves delivering electrical current to the vagal sympathetic complex in patients experiencing heart failure. The therapy has shown promise but the mechanisms by which any benefit accrues is not understood. In this paper we model the response to increased levels of stimulation of individual components of the vagal sympathetic complex as a differential activation of each component in the control of heart rate. The model provides insight beyond what is available in the animal experiment in as much as allowing the simultaneous assessment of neuronal activity throughout the cardiac neural axis. The results indicate that there is sensitivity of the neural network to low level subthreshold stimulation. This leads us to propose that the chronic effects of vagal nerve stimulation therapy lie within the indirect pathways that target intrinsic cardiac local circuit neurons because they have the capacity for plasticity

Inferring mechanisms of copy number change from haplotype structures at the human DEFA1A3 locus

Background: The determination of structural haplotypes at copy number variable regions can indicate the mechanisms responsible for changes in copy number, as well as explain the relationship between gene copy number and expression. However, obtaining spatial information at regions displaying extensive copy number variation, such as the DEFA1A3 locus, is complex, because of the difficulty in the phasing and assembly of these regions. The DEFA1A3 locus is intriguing in that it falls within a region of high linkage disequilibrium, despite its high variability in copy number (n = 3–16); hence, the mechanisms responsible for changes in copy number at this locus are unclear. Results: In this study, a region flanking the DEFA1A3 locus was sequenced across 120 independent haplotypes with European ancestry, identifying five common classes of DEFA1A3 haplotype. Assigning DEFA1A3 class to haplotypes within the 1000 Genomes project highlights a significant difference in DEFA1A3 class frequencies between populations with different ancestry. The features of each DEFA1A3 class, for example, the associated DEFA1A3 copy numbers, were initially assessed in a European cohort (n = 599) and replicated in the 1000 Genomes samples, showing within-class similarity, but between-class and between-population differences in the features of the DEFA1A3 locus. Emulsion haplotype fusion-PCR was used to generate 61 structural haplotypes at the DEFA1A3 locus, showing a high within-class similarity in structure. Conclusions: Structural haplotypes across the DEFA1A3 locus indicate that intra-allelic rearrangement is the predominant mechanism responsible for changes in DEFA1A3 copy number, explaining the conservation of linkage disequilibrium across the locus. The identification of common structural haplotypes at the DEFA1A3 locus could aid studies into how DEFA1A3 copy number influences expression, which is currently unclear

Contributions of greenhouse gas forcing and the Southern Annular Mode to historical Southern Ocean surface temperature trends

We examine the 1979-2014 Southern Ocean (SO) sea surface temperature (SST) trends simulated in an ensemble of coupled general circulation models and evaluate possible causes of the models’ inability to reproduce the observed 1979-2014 SO cooling. For each model we estimate the response of SO SST to step changes in greenhouse gas (GHG) forcing and in the seasonal indices of the Southern Annular Mode (SAM). Using these step-response functions, we skillfully reconstruct the models’ 1979-2014 SO SST trends. Consistent with the seasonal signature of the Antarctic ozone hole and the seasonality of SO stratification, the summer and fall SAM exert a large impact on the simulated SO SST trends. We further identify conditions that favor multidecadal SO cooling: 1) a weak SO warming response to GHG forcing; 2) a strong multidecadal SO cooling response to a positive SAM trend; 3) a historical SAM trend as strong as in observations

Accurate measurement of gene copy number for human alpha-defensin DEFA1A3

Background: Multi-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technical difficulty of large-scale but accurate typing of genomic copy number. The copy-variable alpha-defensin locus DEFA1A3 on human chromosome 8 commonly varies between 4 and 10 copies per diploid genome, and presents considerable challenges for accurate high-throughput typing. Results: In this study, we developed two paralogue ratio tests and three allelic ratio measurements that, in combination, provide an accurate and scalable method for measurement of DEFA1A3 gene number. We combined information from different measurements in a maximum-likelihood framework which suggests that most samples can be assigned to an integer copy number with high confidence, and applied it to typing 589 unrelated European DNA samples. Typing the members of three-generation pedigrees provided further reassurance that correct integer copy numbers had been assigned. Our results have allowed us to discover that the SNP rs4300027 is strongly associated with DEFA1A3 gene copy number in European samples. Conclusions: We have developed an accurate and robust method for measurement of DEFA1A3 copy number. Interrogation of rs4300027 and associated SNPs in Genome-Wide Association Study SNP data provides no evidence that alpha-defensin copy number is a strong risk factor for phenotypes such as Crohn’s disease, type I diabetes, HIV progression and multiple sclerosis