Cyclic AMP signalling pathways in the regulation of uterine relaxation

Studying the mechanism(s) of uterine relaxation is important and will be helpful in the prevention of obstetric difficulties such as preterm labour, which remains a major cause of perinatal mortality and morbidity. Multiple signalling pathways regulate the balance between maintaining relative uterine quiescence during gestation, and the transition to the contractile state at the onset of parturition. Elevation of intracellular cyclic AMP promotes myometrial relaxation, and thus quiescence, via effects on multiple intracellular targets including calcium channels, potassium channels and myosin light chain kinase. A complete understanding of cAMP regulatory pathways (synthesis and hydrolysis) would assist in the development of better tocolytics to delay or inhibit preterm labour. Here we review the enzymes involved in cAMP homoeostasis (adenylyl cyclases and phosphodiesterases) and possible myometrial substrates for the cAMP dependent protein kinase. We must emphasise the need to identify novel pharmacological targets in human pregnant myometrium to achieve safe and selective uterine relaxation when this is indicated in preterm labour or other obstetric complications

Thermodynamic Additivity of Sequence Variations: An Algorithm for Creating High Affinity Peptides Without Large Libraries or Structural Information

BACKGROUND: There is a significant need for affinity reagents with high target affinity/specificity that can be developed rapidly and inexpensively. Existing affinity reagent development approaches, including protein mutagenesis, directed evolution, and fragment-based design utilize large libraries and/or require structural information thereby adding time and expense. Until now, no systematic approach to affinity reagent development existed that could produce nanomolar affinity from small chemically synthesized peptide libraries without the aid of structural information. METHODOLOGY/PRINCIPAL FINDINGS: Based on the principle of additivity, we have developed an algorithm for generating high affinity peptide ligands. In this algorithm, point-variations in a lead sequence are screened and combined in a systematic manner to achieve additive binding energies. To demonstrate this approach, low-affinity lead peptides for multiple protein targets were identified from sparse random sequence space and optimized to high affinity in just two chemical steps. In one example, a TNF-α binding peptide with K(d) = 90 nM and high target specificity was generated. The changes in binding energy associated with each variation were generally additive upon combining variations, validating the basis of the algorithm. Interestingly, cooperativity between point-variations was not observed, and in a few specific cases, combinations were less than energetically additive. CONCLUSIONS/SIGNIFICANCE: By using this additivity algorithm, peptide ligands with high affinity for protein targets were generated. With this algorithm, one of the highest affinity TNF-α binding peptides reported to date was produced. Most importantly, high affinity was achieved from small, chemically-synthesized libraries without the need for structural information at any time during the process. This is significantly different than protein mutagenesis, directed evolution, or fragment-based design approaches, which rely on large libraries and/or structural guidance. With this algorithm, high affinity/specificity peptide ligands can be developed rapidly, inexpensively, and in an entirely chemical manner

From people with dementia to people with data: Participation and value in Alzheimer’s disease research

This paper examines the dynamic relationship between data, participation and value through an analysis of developments in Alzheimer’s disease research. Alzheimer’s disease has risen rapidly up national and international policy agendas, particularly in Europe and North America. Research funding and initiatives have proliferated, many of which emphasise the potential value associated with existing data sources. The paper argues that the potential of these initiatives lies not only in realising the value of data through circulation, exchange and recombination, but in restructuring of the relations of data production and use, notably through the extension and intensification of research participation. As Alzheimer’s research focuses away from clinical settings and symptomatic “people with dementia”, participants in existing research studies are re-imagined as potential participants in future research studies, as “people with data”. Building on analyses of the role of clinical labour in the production of biovalue, the paper argues that reworked relations of data re-use and re-production suggest the ongoing and repeated attachments between data and bodies involved in the production of value. It concludes that this raises questions related to the study of research participation, and requires revisiting discussions about the appropriate representation of research participant interests

Healthy Citizenship beyond Autonomy and Discipline: Tactical Engagements with Genetic Testing

In recent decades a model of healthy citizenship has emerged, which construes citizens as autonomous, responsible and active participants in the management of their health. While proponents view this as an empowering discourse, critics claim that it creates new forms of discipline and social control. This article argues that there is a need for a shift in the conceptual framework surrounding this discussion – beyond autonomy versus discipline understood as heteronomy – because it obscures the many ways in which individuals engage with healthy citizenship discourse that are not governed by principles of autonomous choice and that do not corroborate fears of normalization and discipline. Michel de Certeau’s theory of the creative tactics of everyday life is offered as a useful alternative framework, insofar as it is concerned less with individual autonomy than with the rendering ‘habitable’ of a given space. Drawing on existing empirical research on people’s engagements with genetic risk information, four tactics are identified that escape both healthy citizenship discourse and its critique: translation; selective mobilization; non-disclosure; and a refusal to engage. Thinking in terms of tactics and habitability, it is argued, provides a vocabulary with which to articulate other modes of reasoning, action and moral conduct that are at work